Cancer Research in Switzerland

Cancer Research in Switzerland A publication of the Swiss Cancer League and the Foundation Cancer Research Switzerland on their funded research projects 2009/2010 Edition 2011

Imprint Swiss Cancer League and Foundation Cancer Research Switzerland. All rights reserved by the Scientific office of the Swiss Cancer League and the Cancer Research Switzerland, including the right to reproduce this publication or portions in any form. Publisher and information: Scientific Office Swiss Cancer League Effingerstrasse 40 P. O. Box 8219 CH-3001 Bern Phone +41 (0)31 389 91 16 Fax +41 (0)31 389 91 62 scientific-office@swisscancer.ch www.swisscancer.ch Publication date: November 2009 Edition German: 4400 Ex. Edition French: 1600 Ex. Edition English: 500 Ex. Responsible: Rolf Marti, PhD Head of Scientific Office Swiss Cancer League, Bern Editor: Wolfgang Wettstein Public Relations Consultant BR-SPRV, Zurich w.wettstein@sunrise.ch Kurt Bodenmüller Swiss Cancer League, Bern French translation: Sophie Neuberg, Berlin English translation: Ellen Russon, East Sandwich, Massachusetts, USA Images: Reto Camenisch, Bern Design: Atelier Richner, Visuelle Gestaltung, Bern www.atelierrichner.ch Print: Ast & Fischer AG, Wabern This edition of the report Cancer Research in Switzerland and also the 2009, 2006 and 2004 editions can be downloaded as a PDF file at: www.swisscancer.ch/researchreport This publication is also available in German and French at: www.swisscancer.ch/researchreport Printed on non-chlorine-bleached paper. Reto Camenisch (*1958) is a photographer and head of photography studies at MAZ the Swiss School of Journalism in Lucerne. Camenisch has shown mainly portrait and landscape photographs at national and international exhibitions since 1983. He works exclusively in analogue photography using large format cameras. His work has been published in diverse monographs: 1993 Bürgerbilder, 1997 Bluesland, 2006 Zeit, 2011 Berge Pilger Orte. www.camenisch.ch

Cancer Research in Switzerland

Table of contents 4 Editorial Thomas Cerny and Jakob R. Passweg 6 Better treatment thanks to research funding Rolf Marti 16 Partner organizations and committees Kurt Bodenmüller 20 The Scientific Committee 24 Research awards: Honouring outstanding cancer researchers 26 100 years of the fight against cancer in Switzerland 27 Does Switzerland need a new National Cancer Programme? Thoughts on research and therapy Richard Herrmann 31 Research funding by the cantonal cancer leagues Rolf Marti 33 List of funded research projects, institutions, and programmes in 2009/2010 42 Programme research: Supporting translational and clinical research Kurt Bodenmüller 44 Collaborative Cancer Research Projects (CCRP) List of funded research projects The funded research projects in brief 49 International Clinical Cancer Research Groups (ICP) List of funded research groups The funded research groups in brief

Basic biomedical research 55 Cancer stem cells: The origin of cancer? Lukas Sommer 59 List of completed research projects from July 2008 to December 2010 63 Presentation of completed research projects from July 2008 to December 2010 93 List of approved research projects in 2009/2010 97 Presentation of approved research projects in 2009/2010 Clinical research 115 Challenges for clinical cancer research in Switzerland Beat Thürlimann and Arnoud Templeton 120 List of completed research projects from July 2008 to December 2010 124 Presentation of completed research projects from July 2008 to December 2010 153 List of approved research projects in 2009/2010 156 Presentation of approved research projects in 2009/2010 Psychosocial research 171 Palliative care research in Switzerland Steffen Eychmüller 178 List of completed research projects from July 2008 to December 2010 179 Presentation of completed research projects from July 2008 to December 2010 187 List of approved research projects in 2009/2010 188 Presentation of approved research projects in 2009/2010 Epidemiological research 193 Epidemiological studies on mobile telephones and cancer Martin Röösli and Kerstin Hug 198 List of completed research projects from July 2008 to December 2010 198 Presentation of completed research projects from July 2008 to December 2010 201 List of approved research projects in 2009/2010 202 Presentation of approved research projects in 2009/2010

Editorial 4 For more than 100 years the Swiss Cancer League has been supporting cancer research in academia. And for the past 20 years, it has been doing so together with the Foundation Cancer Research Switzerland. Their goal is to support the highest quality research projects so as to achieve continuous advancements in order to better prevent cancer, to detect the disease earlier, to treat it more successfully, or at least to better alleviate the effects of cancer. For both organizations, the main focus of their funding strategy is patient-centred research. We are very pleased to report that we were able to invest new record sums in cancer-specific research in the years 2009 and 2010. In this period the number of research proposals submitted and the amount of funding applied for also reached new record highs. This trend began already 10 years ago: Whereas the amount of funding applied for tripled in the last 10 years, it was at least possible to double the amount of the funds granted. Here we would like to express a special note of thanks to the members of the Scientific Committee for their outstanding work. This fourth edition of the cancer research report presents the results of the completed research projects and the topics studied by the projects funded. Two changes here are worth mentioning: For the first time, the report presents research funding by the Cancer League as a whole that is, the projects and funds of the Swiss Cancer League along with those of the cantonal cancer leagues. Also new as of 2009 is that the Foundation Cancer Research Switzerland is responsible for distributing the funds to the researchers. Oncosuisse now focuses on strategy and

Thomas Cerny Jakob R. Passweg policy work and was in charge of developing the second National Cancer Programme for the period 2011 2015 that was presented to the public in April 2011. We have kept the same appearance of the publication. This time, photographs by the well-known Bernese photographer Reto Camenisch design and structure the report. The portraits and landscape photographs are from Camenisch s monograph, Berge Pilger Orte, taken in 2009 on a hiking trip through northern India, Nepal, and Tibet. In closing, we would like to extend heartfelt thanks to all of the donors for placing their trust in us over the last years and supporting our work so generously; all of the researchers for their great efforts in the fight against cancer; and all of the people who worked on this edition of the cancer research report. Prof. Dr. Thomas Cerny, MD President of the Foundation Cancer Research Switzerland Prof. Dr. Jakob R. Passweg, MD President of the Swiss Cancer League 5

Better treatment thanks to research funding 6 In the last two years, the Swiss Cancer League (SCL) and Foundation Cancer Research Switzerland (CRS) once again provided record sums for funding cancer research in Switzerland: CHF 12.4 million in 2009 and 15.9 million in 2010. This was made possible by the contributions of the many charitable donors, to whom we extend our thanks. Their donations are helping to improve cancer prevention, detection, and treatment. Funding cancer research is one of the core tasks of the partner organizations Swiss Cancer League and Foundation Cancer Research Switzerland. The focus is on high-quality and patient-centred research conducted at universities, hospitals, and academic research institutes. The SCL is engaged in the entire range of the fight against cancer: It supports and advises persons with cancer and their relatives, works towards early detection and prevention of cancer, and funds cancer research. The SCL is a non-profit organization, and a good 11% percent of its financial means goes towards funding research. As its name implies, the CRS, which is also financed by charitable donations, focuses exclusively on funding research. Professional and efficient utilization of resources The two organizations work together closely. The Scientific Office is the competence centre and operational hub for research funding and is responsible for the call for and the review of proposals and quality control of the funded research projects. The Scientific Office is supported by renowned scientists who provide their extremely valuable services for very little pay. As members of the Scientific Commit- tee they review the research proposals submitted according to clearly defined scientific criteria. With this, the Scientific Committee assures the high quality of the research in the framework of the competition for funding (see the article on the Scientific Committee on page 20). The SCL and CRS have pooled their resources by having one Scientific Office and one Scientific Committee for the two organizations. This makes research funding that meets the highest international quality standards possible, as confirmed by world-renowned universities such as ETH Zurich. It also minimizes administrative costs and makes efficient utilization of the charitable donations feasible, so that the greatest possible portion of the funds available can be put into the qualitatively best research projects. Research for patient benefit One in three people in Switzerland will develop some form of cancer during their lifetime. And unfortunately, soon more people will die of cancer than of any other disease. Directly or indirectly, we are all affected by cancer. Many patients with cancer and their families place their hopes in cancer research and await improvements in treatment options and chances of a cure. Supporting cancer research is also one of the most important concerns of the charitable donors. Rolf Marti, PhD Head of the Scientific Office, Swiss Cancer League

The main focus of the research funding policy of the boards of the SCL and CRS is patient-centred research, or research that puts a priority on the needs of patients. Specifically, this means research funds are mainly granted to projects that aim to deliver findings that will lead to direct benefits for people affected by cancer improvements in prevention, diagnosis, and treatment or improvements in dealing with the disease. Clinical research stands in the foreground of the patient-centred research funding. In addition, projects are funded in the areas of psychosocial research, epidemiology, nursing sciences, prevention, public health, and cancer care and outcome research (that is, research on the quality, effectiveness, and cost control of medical care). Basic research, which lies at the other end of the research spectrum, delivers findings on the biological and molecular mechanisms of the development and spread of cancer. Based on the ever improving understanding of the different types of cancer, new and innovative methods in diagnosis and treatment can be developed over the longer term. New record sums for research The partner organizations SCL and CRS provided new record levels of funding for research in 2009 and 2010. In those two years the total in funding for cancer research projects and organizations, research programmes, and bursaries was CHF 27.6 million, with an annual average of CHF 13.8 million. A total of 112 innovative research projects covering a broad range of topics as well as three Swiss research organizations were supported (Figure 1). Not included in these figures are contributions made to other projects. Also not included in these figures are the approximately 50 research projects that are funded by the cantonal and regional cancer leagues to the amount of CHF 4.2 million annually; this funding is included in this report for the first time (see page 31). These above-average levels of funding were made possible by the generous contributions of the donors. The new record sums are also due to another utilization of reserves of the CRS and to several large bequests. 7 Figure 1 Cancer research funding by the partner organizations Swiss Cancer League (SCL) and Foundation Cancer Research Switzerland (CRS) (independent research projects, bursaries, programme research, Swiss organizations) since the founding of CRS in 1990 Total sum in million CHF: 42.6 (SCL), 131.4 (CRS) Amount (in million CHF) 16 14 11,5 13,1 12 10 8 6 4 2 0 3,5 3,4 2,2 2,7 2,4 3,2 1,6 1,7 1,6 3,6 3,9 2,3 4,4 1,7 1,9 5,1 2,7 3,9 4,9 1,6 1,7 2,0 5,8 6,1 1990 91 92 93 94 95 96 97 98 99 2000 01 02 03 04 05 06 07 08 09 2010 8,9 11,8 9,2 1,4 1,1 1,2 1,3 9,5 2,1 3,1 8,9 9,1 2,6 2,9 2,4 Swiss Cancer League (SCL) Cancer Research Switzerland (CRS)

8 The funding in numbers Total spending on cancer research was CHF 12.4 million in 2009 and CHF 15.9 million in 2010 (Table 1). As in the previous reporting period (2006 2008), about 80 % of the funds came from CRS and 20 % from the SCL. The number of submitted grant applications in independent project research was 140 in 2009 and 156 in 2010, which also sets new records. As compared to the previous reporting period (2006 2008), this represented an increase in the number of applications per year of over 10 %. In 2009 and 2010, 31% of the funding applied for was granted (total applied for: CHF 90.7 million; total granted: CHF 28.3 million). Of the 370 grant applications submitted in total, 158 applications, or about 53 %, were approved for funding. These figures include all grant applications, including applications for support for other projects. Distribution of cancer research spending On average, 78 % of the funding went to independent research projects; 5 % went to persons receiving bursaries; 2 % went to other projects. 6 % of the funds went to research projects in the programme Collaborative Cancer Research Projects (CCRP). In new spending this time, 9 % of the funds went to research organizations as research contributions for basic services. Taking the funds for research programmes and organizations together, it can be seen that the allocation of the research funds once again remained relatively constant compared to the previous years. On average, the annual funding for independent project research increased by about 10 %, from CHF 10 million in the period 2006 2008 to CHF 11 million in the period 2009 2010. The discontinued pro- Table 1 Research funding overview Number of grant applications and amount applied for; number of grants and amounts granted in 2009/2010 (all funding areas) Independent research projects Bursaries Research programmes (ICP/CCRP) Research organizations Other* Total 2009 Number of grant applications 140 6 1 3 20 170 Number of grants 44 5 0 3 17 69 Amount applied for (in thousand CHF) 37 896 743 884 1 260 425 41 208 Amount granted (in thousand CHF) 10 198 557 0 1 260 348 12 363 Proportion of total funding (in %) 82 % 5 % 0 % 10 % 3 % 100 % 2010 Number of grant applications 156 10 1 3 30 200 Number of grants 53 8 2 3 23 89 Amount applied for (in thousand CHF) 45 070 1 138 713 1 710 813 49 444 Amount granted (in thousand CHF) 11 899 826 1 597 1 260 351 15 933 Proportion of total funding (in %) 75 % 5 % 10 % 8 % 2 % 100 % Average per year (2009 and 2010) Number of grant applications 148 8 1 3 25 185 Number of grants 49 7 1 3 20 79 Amount applied for (in thousand CHF) 41 483 941 799 1 485 619 45 326 Amount granted (in thousand CHF) 11 049 692 799 1 260 350 14 148 Proportion of total funding (in %) 78 % 5 % 6 % 9 % 2 % 100 % * Funding for scientific conferences, workshops, international organizations

gramme research funding decreased by 64 %, from CHF 2.2 million in 2006 2008 to CHF 0.8 million in 2009 2010. This benefitted the contributions to the research organizations, to which an annual average of CHF 1.3 million were allocated in 2009 2010. As compared to the previous recording period, 73 % more funding went to persons receiving bursaries, and funding for other projects increased slightly by about 10 %. Other indicates for the most part financial support of scientific and medical conferences and workshops in Switzerland and contributions to international organizations such as EORTC Charitable Trust, the foundation of the European Organisation for Research and Treatment of Cancer. Figure 2 shows the two partner organizations distribution of funds to the cantons and the cantonal institutions in the years 2009 and 2010. Funding of independent research projects: Distribution of spend and grant approval success rate The average funding of independent project research was CHF 11 million per year (Table 2). At 80 % of total spend, this is by far the most important area of research funding. Allocating the lion s share of the funding to independent project research is in accordance with the strategic guidelines set by the SCL and CRS boards. Per year an average of 148 submitted grant applications were approved for funding in the period 2009 2010, which is a grant approval success rate of 33 %. Of the average CHF 41.5 million in funding applied for each year, CHF 11 million were granted, which is a monetary grant approval success rate of 27 %. Compared to the period 2006 2008, this represents a not insignificant decrease of 8 % in the grant approval success rate for projects and a decrease of 5 % in funds. This was the case even though in the period 2009 2010 more funding was available (over CHF 1 million more) for independent project research. The lower grant approval success rate can be explained by the increase in the number of ap plications submitted and the amount of funding applied for. For purposes of comparison: According to the 2010 annual report of the Swiss National Science Foundation (SNSF) the SNSF grant approval success rate in project funding in biology and medicine was 49 % for number of applications submitted and approved and 45 % for amount of funding applied for and amount of funding granted. Once again, the greater part of all requests for funds in independent project research (58%) came from the basic biomedical research sector. Again, only 24 % of the funding applied for was granted (2009: 22 %; 2010: 26 %), even though after the review process an increased number of applications were recommended for funding. This is a consequence of the quota described below, which targets increased funding of patient-centred research. Clinical research includes research projects with patients and also laboratory research using human biological material. In the area of clinical research 30 % of the funds applied for were granted (2009: 32 %; 2010: 27 %). The lowest grant approval success rate was in the area of psychosocial research; here 15 % of the funds applied for were granted (2009: 26 %; 2010: 8 %). This was mainly due to the relatively large number of grant applications submitted that did not pass the evaluation process according to international standards. The highest success rate for grant approval was in the area of epidemiological research: Here, 55 % of the funds applied for were granted (2009: 64 %; 2010: 52 %). Comparing the number of approved applications to the number of submitted applications, the grant approval success rates in the different sectors were: 30 % in basic research, 35 % in clinical research, 27 % in psychosocial research, and 71% in epidemiological research. The funding spend for independent research projects and patient-centred research was higher in the last two years than in the previous reporting period: It increased from CHF 5.2 million (2006 2008) to CHF 5.9 million (2009 2010) annually for basic research and from CHF 4.8 million (2006 2008) to CHF 5.2 million (2009 2010) per year for clinical, psychosocial, and epidemiological research. New ways to support excellent projects There are two deciding factors for the number of research projects approved for funding and for the amount of the funding for the projects that the SCL and CRS support each year: the international quality criteria of proposal evaluation and the monies available for funding. It is a difficult situation when the Scientific Committee rates projects as high in quality and recommended for a grant, but the boards cannot approve funding because there is not enough money. 9

Figure 2 Distribution of cancer research funding to the cantons by Swiss Cancer League and Foundation Cancer Research Switzerland in 2009/2010 Canton Number of Amount in Percentage projects thousand of total CHF AG Cantonal Hospital/UAS/PSI 5 212 100 Total 5 212 1 10 BE SAKK/IBCSG/SPOG 7 2 567 46 University/Inselspital 18 3 037 54 Total 25 5 604 21 BL-BS FMI 5 760 15 University/University Hospital 18 4 249 83 Bursaries and awards 2 119 2 Total 25 5 128 19 GE University/University Hospital 10 2 085 95 Bursaries and awards 3 104 5 Total 13 2 189 8 NE CSEM 1 135 100 Total 1 135 0 SG Cantonal Hospital 3 122 43 Bursaries and awards 2 165 57 Total 5 287 1 TI Hospitals 5 593 51 IOSI/SENDO/IELSG 7 540 47 Bursaries and awards 1 26 2 Total 13 1 159 4 VD ISREC/EPFL 8 2 142 35 University/CHUV 15 3 636 60 Bursaries and awards 3 293 5 Total 26 6 071 22 VS IRO 1 197 100 Total 1 197 1 ZH ETHZ 6 488 8 University/University Hospital 26 5 698 91 Bursaries and awards 2 65 1 Total 34 6 251 23 Total 27 233 100 in thousand CHF 0 2 500 5 000 7 500 Abbreviations AG UAS = University of Applied Sciences PSI = Paul Scherrer Institute BE SAKK = Swiss Group for Clinical Cancer Research IBCSG = International Breast Cancer Study Group SPOG = Swiss Paediatric Oncology Group BL-BS FMI = Friedrich Miescher Institute NE CSEM = Swiss Center for Electronics and Microtechnology TI IOSI = Oncology Institute of Southern Switzerland SENDO = South European New Drug Organisation IELSG = International Extranodal Lymphoma Study Group VD ISREC = Swiss Institute for Experimental Cancer Research EPFL = Swiss Federal Institute of Technology Lausanne CHUV = University Hospital Lausanne VS IRO = Institute for Research in Ophthalmology ZH ETHZ = Swiss Federal Institute of Technology Zurich

Table 2 Distribution of funds for independent research projects 11 Basic biomedical research 2009 2010 Average per year Number of grant applications 74 88 81 Amount applied for (in thousand CHF) 21 632 26 611 24 122 (in %) 57 % 59 % 58 % Number of grants approved 19 29 24 Amount granted (in thousand CHF) 4 796 6 998 5 897 (in %) 47 % 59 % 53 % Clinical research Number of grant applications 45 46 46 Amount applied for (in thousand CHF) 12 387 11 450 11 919 (in %) 33 % 25 % 29 % Number of grants approved 17 15 16 Amount granted (in thousand CHF) 3 964 3 139 3 552 (in %) 39 % 26 % 32 % Psychosocial research Number of grant applications 15 14 15 Amount applied for (in thousand CHF) 2 717 4 298 3 508 (in %) 7 % 10 % 8 % Number of grants approved 4 4 4 Amount granted (in thousand CHF) 695 364 530 (in %) 7 % 3 % 5 % Epidemiological research Number of grant applications 6 8 7 Amount applied for (in thousand CHF) 1 160 2 711 1 936 (in %) 3 % 6 % 5 % Number of grants approved 4 5 5 Amount granted (in thousand CHF) 743 1 398 1 071 (in %) 7 % 12 % 10 % All projects Number of grant applications 140 156 148 Amount applied for (in thousand CHF) 37 896 45 070 41 483 Number of grants approved 44 53 49 Amount granted (in thousand CHF) 10 198 11 899 11 049 53 15 32 (in %)

12 In the period 2009 2010 there were 43 grant applications that were approved but not funded (ABNF) (Table 3). Biomedical research was the area that was the most affected by this problem, with 34 grant applications that were ABNF. In clinical research there were eight ABNF applications and in psychosocial research only one. In the area of epidemiological research, all projects that the Scientific Committee deemed worthy of funding were supported. These figures for ABNF grant applications show clearly that more money is needed for the funding of high-quality research projects. The two partner organizations aim to apply new methods in fundraising, such as via cooperation with partners in industry or with foundations. As a new option, project-specific donations are now possible, which means that a partner can support a research project that has already been evaluated by the Scientific Committee and judged worthy of funding and that matches the partner s aims in terms of content or objectives. Table 3 High-quality research projects approved but not funded (ABNF) 2009 2010 Average per year Basic biomedical research Number of ABNF applications 14 20 17 in % of all ABNF 82 % 77 % 80 % Amount not granted (in thousand CHF) 2 860 4 227 3 544 in % of all ABNF 86 % 84 % 85 % Clinical research Number of ABNF applications 3 5 4 in % of all ABNF 18 % 19 % 18 % Amount not granted (in thousand CHF) 457 656 557 iin % of all ABNF 14 % 13 % 13 % Psychosocial research Number of ABNF applications 0 1 1 in % of all ABNF 0 % 4 % 2 % Amount not granted (in thousand CHF) 0 167 84 in % of all ABNF 0 % 3 % 2 % Epidemiological research Number of ABNF applications 0 0 0 in % of all ABNF 0 % 0 % 0 % Amount not granted (in thousand CHF) 0 0 0 in % of all ABNF 0 % 0 % 0 % All projects Number of ABNF applications 17 26 22 Amount not granted (in thousand CHF) 3 317 5 050 4 184 85 2 13 (in %) Example: Due to a lack of funds 20 projects in basic research could not be funded in 2010, even though they were rated as excellent in quality by the Scientific Committee and recommended for funding (= approved but not funded, ABNF). For these 20 projects, the grant amount applied for was CHF 4.2 million (in total). Hence in the area of basic research, the percentage of ABNF grant applications was 77 % with regard to number of grant applications and 84 % with regard to the amount of grant money applied for.

Funding patient-centred research Patient-centred research is essential for continuous improvement of the medical and psychosocial care of patients with cancer. Central here is clinical research conducted independently of the pharmaceutical industry. For example, very important for patients are research studies on treatment optimization, which aim to find the optimal combination and sequencing in time of existing treatment options, such as chemotherapy, radiation, and surgery, depending on type of cancer, stage of cancer, and the patient. Patientcentred research also includes psychosocial research, which focuses on the psychological and social consequences of cancer and aims to find ways to improve patients quality of life. Epidemiological research studies the prevalence and incidence of cancers in the population and analyzes the factors that affect cancer risk, such as age, sex, smoking, diet, exercise, social network, and environmental factors. Nursing research focuses on improving the care and support of patients with cancer and their families. The boards of the SCL and CRS have been striving for almost 10 years to increase the funding of patient-centred research. In past years, various instruments were introduced, tested, and continuously critically evaluated. One instrument in particular quotas has proved its worth, but other measures that did not have the desired effect have been discontinued or replaced by new ones. Quotas Within the area of independent research projects, 60 % of the funding is earmarked for patient-centred research. Two-thirds of that (or 40 % of the total funds for independent research projects) are reserved for clinical research and one-third (20% of the total funds) for research in the psychosocial area, nursing sciences, epidemiology, prevention, public health, health care and outcomes research. The remaining 40 % of funding for independent research projects is for basic research.

14 Quotas were introduced in 2002 and have since proved to be an effective instrument for increased support of patient-centred research; they are planned to remain in place in the future. Whereas in 2001, 2002, and 2003 35 % of the funds for independent project research went to patient-centred research and 65 % to basic research, the cumulative percentage of funds for clinical, psychosocial, and epidemiological research has since been at a much higher level and a stable one of 45 % and more since 2004 (Table 4). At the same time, it is apparent that this instrument alone is not sufficient to achieve the quota of 60 % for patient-centred research. This is especially due to the fact that too few grant applications have been submitted from these areas that meet the high standards of quality. And the most heavily weighted criterion in the decision to fund research is still the criterion of highest quality research. for funding, which is a success rate of only 21%. For this reason, this instrument, which also entailed a lot of effort for the evaluation process, was discontinued in 2010. Programme research In 2003 two special research programmes were launched: Collaborative Cancer Research Projects (CCRP) and International Clinical Cancer Research Groups (ICP). The CCRP programme provided targeted funding to translational research: Through supporting close collaboration between basic and clinical researchers, the aim was for basic research to move faster from discoveries in the laboratory to actual clinical applications. The ICP programme supported already existing international research collaborations that are coordinated by Switzerland (see also the section on programme research on page 42). Simplified submission procedure To lower the threshold for submission of proposals from underrepresented disciplines in patient-centred research a simplified, two-step submission procedure was introduced. This instrument proved to have only limited success. Of the total 105 originally submitted shorter letters of intent in the period 2004 2009, only 22 led to a research project that was approved After the launch of the research programmes, in the period 2004 2010 a total CHF 14.7 million was invested in this instrument, including CHF 10.1 million in six CCRP that are not yet completed. A critical evaluation of the results of the CCRP showed that these projects, which have a longer duration of five years, lock up too large a portion of the total funds available. Moreover, the desired translational added Table 4 Distribution of funds for independent research projects by research area and year 2003 2004 2005 2006 2007 2008 2009 2010 Basic biomedical research Total in million CHF 4,75 6,00 4,18 5,14 6,12 4,35 4,80 7,00 in % 65 % 56 % 49 % 52 % 56 % 48 % 47 % 59 % Clinical research Total in million CHF 2,19 3,31 3,36 3,31 3,85 2,90 3,96 3,14 in % 30 % 31 % 40 % 33 % 35 % 32 % 39 % 26 % Psychosocial research Total in million CHF 0,14 1 0,61 0,74 1,05 0,84 0,7 0,36 in % 2 % 9 % 7 % 7 % 10 % 9 % 7 % 3 % Epidemiological research Total in million CHF 0,22 0,37 0,31 0,74 0 0,93 0,74 1,40 in % 3 % 3 % 4 % 7 % 0 % 10 % 7 % 12 % All projects Total in million CHF 7,30 10,68 8,46 9,93 11,02 9,02 10,20 11,90

value was not clearly discernible. It was also unclear whether the collaborations between laboratory and clinic supported by the CCRP will continue in the longer term. For this reason, there have been no more calls for proposals under the CCRP programme since 2009. Naturally, translational research projects continue to be funded via independent project research. Calls for proposals were also discontinued in 2009 for the ICP programme. Two ongoing ICP will be completed in 2011: the International Childhood Liver Tumour Consortium and the International Extranodal Lymphoma Study Group (IELSG). In total, seven ICP were funded with a total of CHF 4.6 million. This instrument for promoting programme research was replaced by financial contributions to clinical cancer research institutions in Switzerland. Supporting clinical cancer research organizations In 2009 the boards of the SCL and CRS decided to change the strategy regarding support for cancer research organizations: Now, by means of performance agreements, important basic services are funded that diverse organizations perform within clinical cancer research, such as designing study protocols, managing data, obtaining authorizations from ethics committees and Swissmedic, coordinating multi-centre studies and international studies, and others. Through the structural contributions for specific activities, the aim is to reward and ensure the work of the organizations in the longer term. This association is an academic research organization focusing on clinical, patient-centred research in paediatric oncology, particularly in the frame work of national collaborative studies. The SPOG receives CHF 100,000 per year. On the part of CRS, a maximum CHF 2 million, or maximum 20 % of the total research funding budget, is reserved for this instrument. These monies are used by CRS for targeted financial support of five to six research organizations. Dr. Rolf Marti, PhD Rolf Marti has headed the Scientific Office since 2002 and is responsible for research funding. He is a member of the managing board of the Swiss Cancer League and director of Foundation Cancer Research Switzerland. One of the focuses of his work is research policy. Phone +41 (0)31 389 91 45 rolf.marti@swisscancer.ch www.swisscancer.ch/research 15 The following organizations were supported by the SCL in the reporting period 2009 2010: Swiss Group for Clinical Cancer Research (SAKK): This non-profit organization has launched and coordinated clinical cancer trials in Switzerland and abroad since 1965. SAKK comprises a wide network of about 20 Swiss research groups and the SAKK Coordinating Centre in Bern. SAKK receives a contribution of CHF 600,000 per year. International Breast Cancer Study Group (IBCSG): This study group has conducted academic clinical trials in breast cancer since 1977. It is dedicated to improving the treatment of women with breast cancer. IBCSG receives an annual contribution of CHF 560,000. Swiss Paediatric Oncology Group (SPOG):

Partner organizations and committees 16 Brief portrait of the Swiss Cancer League (SCL) The Swiss Cancer League is a charitable, private nonprofit organization. Its work is dedicated towards the following aims: fewer people being diagnosed with cancer, fewer people dying of cancer, more people with cancer treated successfully, and providing care and aid to persons with cancer and their families in all phases of the disease and in dying. It funds cancer research, sensitizes the public to prevention measures, advocates for early diagnosis and treatment, provides advice to persons with cancer and their loved ones, and offers social support. The 20 cantonal cancer leagues are active at the local and regional levels. They provide psychosocial advice and financial support to persons with cancer and their families locally. Most of the funding for the SCL s numerous tasks comes from donations. The SCL funds cancer research, with a special focus on supporting patient-centred research projects. Contact information Swiss Cancer League Effingerstrasse 40 P.O. Box 8219 CH-3001 Bern Phone +41 (0)31 389 91 00 info@swisscancer.ch www.swisscancer.ch Brief portrait of the Foundation Cancer Research Switzerland (CRS) In existence since 1990, the Foundation Cancer Research Switzerland generates donations that help provide funding for all areas of cancer research: basic research, clinical, epidemiological, psychosocial research, and paediatric research (research on childhood cancer). The CRS foundation board is responsible for distributing the funds to the researchers. The funding decisions are based on the recommendations made by the Scientific Committee. The Scientific Committee is made up of experts in cancer research and reviews the research proposals submitted according to clearly defined guidelines. The CRS also supports the development and implementation of measures to fight cancer in Switzerland namely, the National Cancer Programme 2011 2015 (NCP II). Contact information Foundation Cancer Research Switzerland Effingerstrasse 40 P.O. Box 7021 CH-3001 Bern Phone +41 (0)31 389 91 16 info@cancerresearch.ch www.cancerresearch.ch Kurt Bodenmüller Communications manager of the Scientific Office, Swiss Cancer League

New organization of the Foundation Cancer Research Switzerland and Oncosuisse 17 In the fall of 2009 the course was determined for a new strategic and operational direction of the Foundation Cancer Research Switzerland (CRS) and Oncosuisse. The goal of the new organization was to simplify the structures and processes of research funding and to focus on the core competencies of the two organizations. Previously, Oncosuisse had been responsible for awarding the monies generated by the CRS to the researchers. Under the new organization, the CRS foundation board is responsible for this task. To this purpose, a new board was formed and expanded: The board now has one representative each from the Swiss Cancer League (SCL), the Swiss Group for Clinical Cancer Research (SAKK), and the Swiss Paediatric Oncology Group (SPOG), one expert in each of the different research areas, a financial specialist, and further independent persons. Within the framework of the new organization, Oncosuisse, the Swiss Federation Against Cancer founded in 1999, became a simple association. As a platform it focuses on coordinating and representing the strategic policies of the Swiss network working against cancer. Its most important task is developing and implementing the National Cancer Programme 2011 2015 (NCP II). This policy instrument aims to coordinate at the national level and improve cancer research, prevention, early detection, cancer treatment, and coping with the effects of the disease. Since 2011, the NCP II functions as the national guide in the fight against cancer. Oncosuisse is financed by the membership fees of its five partners: CRS, SCL, SAKK, SPOG, and the National Institute for Cancer Epidemiology and Registration (NICER). Contact information Oncosuisse Effingerstrasse 40 CH-3008 Bern Phone +41 (0)31 389 93 00 Fax +41 (0)31 389 92 00 info@oncosuisse.ch www.oncosuisse.ch

The board of the Swiss Cancer League (SCL) In April 2010 Prof. Jakob R. Passweg, MD, was elected president of the Swiss Cancer League. Gilbert Bernard Zulian, MD, is vice-president. The nine members of the SCL board are: 18 Prof. Jakob R. Passweg, MD Head physician of Hematology University Hospital Basel President Since 2007 Lucienne Bigler-Perrotin Manager Geneva Cancer League Since 2009 PD Gilbert Bernard Zulian, MD Head physician of Department of Palliative Medicine Hôpital de Bellerive University Hospital Geneva Vice-president Since 2009 Hans Neuenschwander, MD Medical Director of Palliative Care Regional Hospital of Lugano Since 2010 Gallus Mayer Member of management board Wegelin & Co., Private Bankers St Gallen Treasurer Since 2006 Martin Nobs, lic. phil. Manager Bern Cancer League Since 2009 Irène Bachmann-Mettler Project head of Institute of General Practice and Health Services Research University of Zurich President of Oncology Nursing Society of Switzerland Since 2003 Brigitta Wössmer, PhD Head psychologist of Department of Psychosomatics University Hospital Basel President of Swiss Society of Psycho-Oncology Since 2011 Prof. Daniel Betticher, MD Head physician of Clinic for Medical Oncology Fribourg Cantonal Hospital Since 2006

The board of the Foundation Cancer Research Switzerland (CRS) Prof. Thomas Cerny, MD, has been president of the Foundation Cancer Research Switzerland since 2009, and Prof. Richard Herrmann, MD, is vice-president. The nine members of the CRS board are: Prof. Thomas Cerny, MD Head physician of Medical Oncology/ Hematology Department of Internal Medicine Cantonal Hospital St. Gallen President Past President of SCL Since 2009 Eduard Holdener, MD Therwil Independent person Since 2009 19 Prof. Richard Herrmann, MD Former head physician of Clinic for Medical Oncology University Hospital Basel Vice-president Past President of SAKK and representative for clinical cancer research Since 2009 Isabel Lechtman-Mortara Geneva Independent person Since 2009 Pascal Couchepin, lic. iur. Former Federal Councillor Martigny, Switzerland Independent person Since 2010 Gallus Mayer Member of managing board Wegelin & Co., Private bankers St Gallen Financial expert Since 2009 Prof. Matthias Egger, MD Director of Institute of Social and Preventive Medicine University of Bern Representative for epidemiological cancer research Since 2009 PD Nicolas von der Weid, MD Co-head of Paediatric Hematology-Oncology Unit University Hospital Lausanne (CHUV) Past President of SPOG and represen tative for paediatric cancer research Since 2009 Prof. Hans Hengartner, PhD Langnau am Albis Representative for basic cancer research Since 2009

The Scientific Committee 20 Members of the Scientific Committee in 2010 (from left): Felix Niggli, Gerhard Christofori, Primo Schär, Brian A. Hemmings, Maria Blettner, Holger Moch, Martin F. Fey (president), Rolf Marti (head of the Scientific Office), Ellen Benhamou, Freddy Radtke, Martin Pruschy, Adrian Ochsenbein, Cristiana Sessa, Hans-Uwe Simon (not pictured: Kurt Fritzsche and Friedrich Stiefel). The Scientific Committee is responsible for evaluating the research grant applications submitted to the Foundation Cancer Research Switzerland and the Swiss Cancer League by researchers seeking research funding. The committee s peer review process uses strictly defined evaluation criteria (see box, Criteria for high-quality cancer research, page 23). The central criterion is always whether a research project is expected to advance our understanding of cancer prevention, causes, or treatment. The 15 members of the Scientific Committee are recognized experts with outstanding achievements and expertise in all areas relevant to cancer research. Having all of the research areas represented on one committee prevents the formation of specialized subcommittees and also assures funding of research trends in all areas. The members serve on the committee for three years and can be re-elected twice.

The president of the Scientific Committee is Prof. Martin F. Fey, MD. The committee members are representatives of the following research areas: basic biomedical research: 4 members patient-centred clinical cancer research: 2 members laboratory-based clinical cancer research: 2 members epidemiology and cancer prevention: 2 members psychosocial and other cancer research (public health research): 2 members translational cancer research: 2 members Each member of the committee handles on average 20 grant applications per year. More than half of the proposals are in basic research. As the time it takes for members to review basic research proposals has reached an upper limit, it has been decided that an additional representative of the discipline can be voted into the Scientific Committee. The Scientific Committee meets twice a year to discuss in detail the research grant applications that have been reviewed by committee members and by external reviewers (see box, The research grant application review process ). Based on the discussions the committee produces a ranked list of the research proposals that the committee recommends to the boards of the Foundation Cancer Research Switzerland and the Swiss Cancer League for grant approval. As the financial means are limited, it is never possible to approve grants for all proposals that the committee judges to be of good quality and worthy of funding. In the reporting period 2009 2010 there were on average 22 research proposals each year that could not be approved for funding despite their excellent quality. In total the Scientific Committee reviews almost 150 grant applications per year. The research grant application review process The research proposal is submitted to and recorded by the Scientific Office of the Swiss Cancer League. < The grant application is sent for review to two members of the Scientific Committee who are experts in the relevant specialist field (such as basic research or psycho-oncology). < The two Scientific Committee members recommend additional experts as external reviewers. < The Scientific Office asks the external reviewers to review the proposal. < The reviewers evaluate the proposal. Four to six reviews are obtained for each research proposal, two of which are by Scientific Committee members. < The Scientific Office collects the reviews and puts them in a file. < The research proposal is discussed in detail at the bi-annual meeting of the Scientific Committee. < After the meeting, the Scientific Office writes up detailed minutes and creates a list of all proposals ranked according to the committee s recommendations. < The ranking list is forwarded to the boards of the Foundation Cancer Research Switzerland and the Swiss Cancer League, which then decide which proposals will be funded. < The Scientific Office notifies the applicant of the decision. Upon request, the reviews are made available to the applicant in an anonymous form. 21 Operational support for the Scientific Committee s important tasks and responsibility is provided by the Scientific Office of the Swiss Cancer League and the Foundation Cancer Research Switzerland. It organizes the call for and review of proposals and is responsible for quality control of the supported research projects.

Members of the Scientific Committee, 2009/2010 Prof. Martin F. Fey, MD Institute of Medical Oncology University Hospital Bern University of Bern Bern, Switzerland President Since 2006 Brian A. Hemmings, PhD Friedrich Miescher Institute for Biomedical Research (FMI) Basel, Switzerland Since 2003 22 Ellen Benhamou, MD Gustave Roussy Cancer Institute Villejuif Cedex, France Since 2003 Prof. Eugen B. Hug, MD Center for Proton Radiation Therapy Paul Scherrer Institute (PSI) Villigen, Switzerland 2008 2010 Prof. Maria Blettner, PhD Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI) University Medical Center Johannes Gutenberg University Mainz Mainz, Germany Since 2010 Prof. Joachim Lingner, PhD Swiss Institute for Experimental Cancer Research (ISREC) Swiss Federal Institute of Technology Lausanne (EPFL) Epalinges, Switzerland 2003 2010 Paolo Boffetta, MD Unit of Environmental Cancer Epidemiology International Agency for Research on Cancer (IARC) Lyon, France 2005 2009 Prof. Holger Moch, MD Institute of Surgical Pathology University Hospital Zurich Zurich, Switzerland Since 2006 Prof. Gerhard Christofori, PhD Department of Biomedicine University of Basel Basel, Switzerland Since 2004 Prof. Felix Niggli, MD Paediatric Oncology University Children s Hospital Zurich Zurich, Switzerland Since 2002 Prof. Kurt Fritzsche, MD Department of Psychosomatic Medicine and Psychotherapy University Hospital Freiburg, Germany Since 2009 Prof. Adrian Ochsenbein, MD Institute of Medical Oncology University Hospital Bern University of Bern Bern, Switzerland Since 2006

Prof. Martin Pruschy, PhD Department of Radiation Oncology University Hospital Zurich Zurich, Switzerland Since 2010 Prof. Cristiana Sessa, MD Oncology Institute of Southern Switzerland (IOSI) Hospital San Giovanni Bellinzona, Switzerland Since 2000 Prof. Freddy Radtke, PhD Swiss Institute for Experimental Cancer Research (ISREC) Swiss Federal Institute of Technology Lausanne (EPFL) Epalinges, Switzerland Since 2007 Prof. Hans-Uwe Simon, MD, PhD Institute of Pharmacology University of Bern Bern, Switzerland Since 2008 23 Prof. Primo Schär, PhD Department of Biomedicine University of Basel Basel, Switzerland Since 2010 Prof. Friedrich Stiefel, MD Psychiatry Service University Hospital Lausanne (CHUV) Lausanne, Switzerland Since 2007 Criteria for high-quality cancer research The quality of research grant application is evaluated according to the following criteria: Cancer relevance: Is the proposed research project expected to contribute important new observations or knowledge on the causes, prevention, or treatment of cancer? Originality or socio-economic significance: Is the proposed research project original, innovative (basic research projects), or of socio-economic importance (clinical or epidemiological projects)? Choice of methodology: Have the most appropriate methods for the project realization been chosen? Feasibility: Is the project feasible in terms of finances, human resources, and organization? The applicant s previous productivity: What are the applicant s (or the project group s) previous research achievements? How good were the publications?

Research awards: Honouring outstanding cancer researchers 24 Besides supporting research through funding projects, bursaries, and organizations, the Swiss Cancer League regularly gives the Robert Wenner Award for outstanding research work. In addition, each year the Scientific Office of the Swiss Cancer League organizes the call for research grant applications and the evaluation of proposals submitted for the SWISS BRIDGE AWARD. With the awarding of research prizes, the recipients are recognized for their excellent work in cancer research. For the researchers, this recognition means both honour for their previous achievements and incentive for future research efforts. As the greatest part of the award money must be invested in cancer research, research awards allow the recipients to continue their work or to initiate new projects. For the Swiss Cancer League the awarding of research prizes is also a way to inform the public about outstanding industry-independent cancer research. Robert Wenner Award Robert Wenner, a gynaecologist in Basel who died in 1979, endowed the Robert Wenner Award to support cancer researchers under the age of 45. The prize was awarded for the first time in 1985. The award winners receive CHF 100,000, with CHF 80,000 earmarked for an ongoing project and CHF 20,000 as discretionary funds. In 2010 the Robert Wenner Award was given to Prof. Dr. Melody Swartz at the Swiss Federal Institute of Technology Lausanne (EPFL) for her excellent work in basic research on tumour metastasis. No prize was awarded in 2009. Interdisciplinary cancer researcher Melody Swartz is a bioengineer who integrates different modern scientific disciplines in her research. Together with her team she combines cell biology, biochemistry, physiology, bioinformatics, and engineering to study cancer. Her interest centres on the lymphatic system and, specifically, on how tumour cells behave in the lymphatic system. The lymphatic system, which works with the circulatory system, is made up of lymph nodes and lymphatic vessels in which lymph fluid circulates. The lymphatic system transports pathogens to the lymph nodes, where antibodies are produced and an immune response is mounted. The immune response thus depends on the lymphatic system. Cunning cancer cells It is known that cancer cells also utilize lymphatic vessels to spread through the body and form metastases at new sites. However, this process is still largely unknown. Among other things, Swartz is studying how cancer cells move into the lymph vessels. It appears that tumours are able to stimulate the growth of the lymph vessels so that cancer cells can invade them. Also, the lymph vessels appear to actively support the tumour cells in this process. The immune system is fooled, and the cancer cells evade the immune defence.

Swartz wants to find out how tumours accomplish this trick. Using the lymphatic transport mechanisms, she is trying to deliver vaccines and other drugs to the lymph nodes. The drugs are aimed at affecting the immune cells of the lymphatic system and stimulating them to perform their actual task in the organism, which is to destroy cancer cells instead of aiding their spread. Prof. Melody Swartz, PhD Melody Swartz was born in the United States in 1969. She studied at Johns Hopkins University in Baltimore, at Massachusetts Institute of Technology in Cambridge, and at Harvard Medical School. She completed her PhD in chemical engineering in 1998. From 1999 to 2003 she was assistant professor in the Departments of Biomedical Engineering and Chemical Engineering at Northwestern University in Chicago. Since 2003 she has been working at the Institute of Bioengineering at the School of Life Sciences at the Swiss Federal Institute of Technology Lausanne. In 2010 she was appointed full professor of bioengineering. She heads a research team at the Laboratory of Lymphatic and Cancer Bioengineering. Swartz is married and has a son. 25 SWISS BRIDGE Foundation: Supporting outstanding cancer research SWISS BRIDGE was established upon the initiative of Thomas Hoepli, who was formerly managing director of the foundation and today is a member of the foundation board. The purpose of the foundation, which was set up in 1997 with the support of the Swiss Cancer League, is to support high-quality research projects in Switzerland and abroad in the fight against cancer using funds that come from private donors and foundations, such as the Stammbach Foundation in Basel. SWISS BRIDGE has a foundation board, an international scientific committee, a board of patrons, and a loyal circle of supporters and friends. Starting in 2000, each year the foundation has given the SWISS BRIDGE AWARD, totalling CHF 500,000. The award honours researchers whose research work promises to achieve milestones in the study of and in the fight against cancer. The Scientific Office of the Swiss Cancer League organizes the call for research grant applications and the review of the projects submitted for the award. Up to now, the SWISS BRIDGE AWARD has awarded a total of CHF 6.35 million for projects conducted by researchers in Belgium, England, France, Israel, Italy, Norway, Sweden, Spain, and Switzerland. The recipients of the SWISS BRIDGE AWARD in recent years were: 2010 Andrea Alimonti, MD Laboratory of Experimental Oncology, Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland Ronit Satchi-Fainaro, PhD Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Anna Sablina, PhD Department of Molecular and Developmental Genetics, Research Institute VIB, University of Leuven, Leuven, Belgium 2009 Prof. Matthias Egger, MD Institute of Social and Preventive Medicine, University of Bern Prof. Wilhelm Krek, PhD Institute of Cell Biology, ETH Zurich Prof. Stephen C. West. PhD Clare Hall Laboratories, London Research Institute, Cancer Research UK, South Mimms, England Further information: www.swissbridge.ch

100 years of the fight against cancer in Switzerland 26 On the occasion of its centennial in 2010, the Swiss Cancer League published a look at medical history titled Vom Tabu zum Thema? (From taboo to topic?). This interesting read by Daniel Kauz examines central facets of one hundred years of fighting cancer in Switzerland. The structure of the book is novel and unique in that it is not a chronological account starting in 1910 but rather an examination of six different self-contained topics. It investigates the development of treatment options, the institutionalization of cancer research, and the educational and prevention work of the Swiss Cancer League over time. How did interactions with the patients, and thus their status, change? What images and fantasies (mostly frightening) did people associate with cancer? How was it possible to gradually break down the taboo surrounding cancer? And how did the Swiss Cancer League evolve from a small association of medical specialists to an established non-profit organization active in health and research policy? Kauz looks at these and other topics from a perspective of medical history. The volume does not celebrate the Swiss Cancer League as an institution but presents its work in the context of the different topics. This is a highly readable, solid historical account with a modern structure. Kauz, born in 1971, completed a Master s degree in history, German literature and philosophy at the University of Zurich and is the author of several history publications. This richly illustrated volume is available in German and French at bookstores or online at the Swiss Cancer League shop at www.krebsliga.ch/shop. The German edition was published by Schwabe Verlag, and the French edition was published by Editions Attinger. Bibliography Daniel Kauz Vom Tabu zum Thema? 100 Jahre Krebsbekämpfung in der Schweiz 1910 2010 2010. 267 pages, 149 illustrations (85 in colour), 6 tables. Bound. DVD included. CHF 58. /Euro 40.60 ISBN 978-3-7965-2671-8 Schwabe Verlag ISBN 978-3-03754-046-6 EMH Schweizerischer Ärzteverlag Daniel Kauz Du tabou au débat? Cent ans de lutte contre le cancer en Suisse 1910 2010 2010. 255 pages, 149 illustrations (85 in colour), 6 tables. Bound. CHF 58. /Euro 41. ISBN 978-2-940418-16-9 Editions Attinger SA Further information in German at www.krebsliga.ch/ fachbuch or in French at www.liguecancer.ch/ouvrage Kurt Bodenmüller Kurt Bodenmüller is a microbiologist who has worked in the field of science communications since 1997. He worked for many years as a consultant at an international PR company. He has been communications manager at the Scientific Office of the Swiss Cancer League since 2008. Phone +41 (0)31 389 93 31 kurt.bodenmueller@swisscancer.ch www.swisscancer.ch/research

Does Switzerland need a new National Cancer Programme? Thoughts on research and therapy The scientific and medical research conducted in Switzerland is high level. Our medical care is excellent, too also in oncology. So why does Switzerland need a five-year national cancer programme in which research and therapy play an important role? Almost 10 years ago, under the overall control of Oncosuisse the first National Cancer Programme was worked out for the period 2005 2010; it also contained a number of aims in the areas of research and therapy. However, regarding achievement of these aims the end result was sobering. All in all, only little progress could be achieved. This was in part due to the fact that many of the stated aims were set for the more distant future. In April 2011, Oncosuisse launched the second National Cancer Programme for the period 2011 2015. Within cancer research and treatment, we face a number of challenges. Cancer research in the laboratory pursues various aims. For instance, a research study may aim to find out why from a healthy cell that has a defined function and divides only under very controlled conditions a cancer cell develops. This cell evades the normal control mechanisms, divides again and again, invades surrounding tissue and destroys it, separates from its normal united cell structure and spreads via the blood to other organs, where it continues to divide and forms metastases. All of these abnormal characteristics are based on changes in the genetic information (DNA) of these cells; these mutations occur on a huge scale in cancer cells. The stony way from the laboratory to the clinic To be able to intervene therapeutically, we have to know the genetic changes, or mutations, of the cancer cells. Based on this knowledge it is possible to block their effects. If this type of research is conducted using animal experiments or human cell lines in the test tube, the findings may not yet be directly applicable to tumour disease in humans. Although we have model systems that are used to investigate certain mechanisms and processes, their transferability to humans is limited. If we study human tumours, the results are frequently not uniform, as there is mostly considerable variability within the same tumour disease, such as within breast cancer. Moreover, it is very difficult to obtain a sufficiently large number of human tumour tissue samples to allow reliable findings. Consequently, there is a long and difficult way from the results of experimental laboratory research to successful medical treatment of patients, and it is here that we must push ahead more and more. For example, there is a need for more research with human tumour material that is aimed at directly influencing the course of the disease. The aim could be, for instance, to find specific molecular changes. If such markers were known, we could develop new medicines or study the mechanisms of resistance to currently prescribed cancer drugs. Through the latter, more efficient use of these in part very expensive drugs could be made possible and many patients could be spared the side effects of an ineffective 27 Prof. Richard Herrmann, MD President of Oncosuisse and former head physician of the Clinic for Medical Oncology at the University Hospital Basel

28 treatment. This kind of research is called translational. It could also be called bridging research, for it builds bridges between research in the laboratory and the treatment of patients with cancer. Translational research has a bridging function The National Cancer Programme 2011 2015 defines translational research as one of its priorities. For this, closer cooperation is needed among researchers involved on both sides laboratory and hospital. Cooperation at the national level is also needed. Already today, for several cancers that are actually all the same disease such as breast cancer, lung cancer, or colon cancer, it is possible to identify specific subgroups of the particular tumour type on a molecular basis, and they require very different treatments. In this way, suddenly several different new clinical pictures arise. Today there are at least ten different types of lung cancer, for example. As a result, out of one common disease there suddenly emerge several rare diseases. Great cooperative effort is required all the more for their study. With its long-year tradition of cooperative clinical research through the Swiss Group for Clinical Cancer Research (SAKK), Switzerland is predestined to tackle this topic seriously and with the promise of succeeding. Through the collaboration of many committed researchers and physicians a great deal of knowledge and experience will be gathered together that will be crucial in answering important questions for the good of patients with cancer. Both laboratory research and the advances in clinical research should ultimately benefit the patients. However, this pathway of many small steps is subject to constant change. Research findings from the laboratory and from clinical studies always influence each other. The connection between these two branches of research translational research can help us to find out, for example, why a patient s initially successful therapy is suddenly no longer effective. It has been found for many cases of cancer that an effective drug initially docks successfully with the receptor of the tumour cell. However, if the docking site changes due to mutations, the drug becomes ineffective and the tumour cell can continue to grow unhindered. Exact knowledge of these processes allows us to develop new substances whose effectiveness will not be disabled by this resistance mechanism. Complexity demands interdisciplinarity The developments within cancer treatment in the last five to ten years have made the area a great deal more complex and complicated, for several reasons: 1. As mentioned above, there are many more different types of cancer today. Great effort is required for precise diagnosis, and the therapies are different for each type. The use of new medicines is not only costly but also requires detailed knowledge of how the drugs work, the exact guidelines for their use, possible side effects and possible ways to treat or prevent these side effects. 2. If a therapy has failed, for many tumour diseases there is a second option, often called second-line therapy; occasionally there is also a third or fourth line. This also increases the complexity as well as the time required for a patient, because prior to starting any new therapy the health care provider must talk with a patient to provide detailed information.

3. The original order/sequence of the modes of treatment for cancer surgery, radiation therapy, chemotherapy is becoming more and more seldom. Now, the therapy goal determines the mode of treatment to be used in the individual case. This means that chemotherapy a better name is systemic therapy may be the first-line therapy. Surgery can be required at different points in time in the course of the disease, such as to remove metastases. For optimum treatment results, patients medical conditions must be reviewed and discussed at multidisciplinary conferences called tumour boards. The experts in the different medical specialities involved discuss and make a plan for the patients further treatment based on their review of the current clinical findings. In large centres there is a tumour conference of this kind for every cancer type, that is usually scheduled weekly. This promotes the transparency within a centre considerably and increases the quality of treatment. These tumour conferences are very personnelintensive, however. 4. The enormous knowledge gain in clinical cancer research combined with our growing basic understanding of tumour biology inevitably requires subspecialization within medical oncology. No oncologist today can have the needed in-depth grasp of the entire range of the subject. However, to provide patients with cancer in Switzerland with the best possible care and treatment according to the latest research, the structures of patient care must be adapted to this development. For one, we need more centralization, which should not be too difficult in a country with a manageable size like Switzerland and with the help of electronic communications means. For another, we need defined competence centres for rare diseases depending on prevalence perhaps one or two. This would make it possible to build the needed competence in a multidisciplinary way. Research projects with sufficient numbers of patients could be undertaken, among other things through international networking of these competence centres. These measures would boost development in the area of these very rare types of cancer that are often neglected by the pharmaceutical industry.

30 The changes that are needed due to the developments in oncology described above cannot be expected to happen by themselves. For this reason, the National Cancer Programme 2011 2015 demands the necessary structural changes. As physicians and researchers committed to persons with cancer, we see it as our task to inform the public, to push for the needed policy decisions, and to convince our colleagues of the necessity of these changes. Prof. Richard Herrmann, MD Richard Herrmann was head physician of the Clinic for Medical Oncology at the University Hospital Basel from July 1991 to June 2011. From 2004 to 2010 he was president of the Swiss Group for Clinical Cancer Research (SAKK). Since 2009 he has been vicepresident of the Foundation Cancer Research Switzerland and in addition president of Oncosuisse, which is responsible for development and implementation of the National Cancer Programme 2011 2015. herrmannr@uhbs.ch www.oncosuisse.ch National Cancer Programme for Switzerland 2011 2015 The fight against cancer is a complex, multidisciplinary task that requires the coordination of many actors. To this purpose, the cancer organizations in Switzerland, with the support of the federal government and the cantons, have worked out the National Cancer Programme 2011 2015 (NCP II). The NCP II defines 10 areas of priority with specific measures to be followed within each. The programme has chosen an approach that transcends the individual disciplines, for only a complete chain of measures from prevention to early diagnosis to therapy to rehabilitation or palliative care has the chance of achieving effective improvements in the fight against cancer. There are three main goals: Every person living in Switzerland should be equally entitled to the lowest possible cancer risk through prevention and early diagnosis, to appropriate diagnostics and treatment according to the latest findings and psychosocial and where unavoidable palliative care in the case of illness. The NCP II aims to improve quality and to close gaps in services and care. The NCP II presents specific recommendations for the fight against cancer. It is directed at policy decision-makers at federal and cantonal levels, organizations in the health care system, researchers and decision-makers in hospitals and universities, and also the public, which is affected by cancer in many ways. The report presents an overview of the actions and ensures transparency for all actors. www.oncosuisse.ch

Research funding by the cantonal cancer leagues As a federation, the Cancer League comprises 20 cantonal and regional cancer leagues, with the Swiss Cancer League (SCL) as the umbrella organization with headquarters in Bern. In addition to the SCL, eleven of the cantonal cancer leagues provided funds for research in 2009 and 2010: On average per year the cantonal cancer leagues awarded a total of CHF 4.2 million to close to 50 research projects, mostly to projects in their own canton. If needed, cantonal cancer leagues can call upon the support and competence of the SCL in the review of grant applications. Small cantonal cancer leagues without their own research funding activities can help to fund research projects that have already been evaluated and are supported by the SCL. At the policy level, SCL works for good framework conditions for research, especially clinical research. 31 A federation development project was launched in 2009 with the aim to intensify cooperation within the organization as a whole and to offer nationally standardized services to patients. In the context of this process, the area of research funding was also discussed at length. The cantonal cancer leagues and the SCL came to a mutual agreement on the following principles for optimization of the quality, allocation of responsibilities, and services in the area of research funding: Mutual exchange of information on funds, projects, processes, and selection criteria will be improved. Large cantonal cancer leagues that have their own research funding activities will follow mutually determined minimal requirements with regard to the evaluation process and the evaluation criteria used in the review of grant applications. A further goal of the federation development project of the Cancer League is to improve the transparency of supported research projects and their results both within the organization as a whole and for the public, partners, and politics/government. To this purpose, the SCL conducted a written survey of the cantonal cancer leagues in the spring of 2011. In the following, detailed information on research funding by the cantonal and regional cancer leagues in the years 2009 and 2010 is presented. Information is provided not only on research projects funded but also for funding in the broader sense, which includes support given to cancer registries or cancer screening programmes. In principle the cantonal cancer leagues support research projects and institutions in their own cantons. In part the cantonal cancer leagues also supported research projects that the SCL and the Foundation Cancer Research Switzerland evaluated and approved for funding but did not fund in full. Rolf Marti, PhD Head of the Scientific Office, Swiss Cancer League

32 In total, eleven cantonal cancer leagues awarded an average of CHF 4.2 million per year for cancer research. Three-quarters of that amount was given to research by the four largest cantonal cancer leagues Basel, Bern, Geneva, and Zurich. The average number of projects and institutions supported each year was 50 (Table 5). Table 5 Research funding by the cantonal cancer leagues in 2009/2010 Cantonal cancer leagues Number of projects and institutions supported in 2009/2010 Amount granted in 2009/2010 (in CHF) Number of projects and institutions supported, average per year Amount granted, average per year (in CHF) Aargau 3 335 386 2 167 693 Basel 23 1 539 225 12 769 613 Bern 16 920 000 8 460 000 Geneva 15 1 984 270 8 992 135 Grisons 3 65 000 2 32 500 Neuchâtel 2 349 094 1 174 547 Schaffhausen 2 50 000 1 25 000 St. Gallen-Appenzell 3 588 300 2 294 150 Ticino 10 541 560 5 270 780 Thurgau 1 25 000 1 12 500 Zurich 28 1 976 885 14 988 443 Total 106 8 374 720 50 4 187 360

List of funded research projects, institutions, and programmes in 2009/2010 The list shows the financial contributions granted in 2009 and/or 2010. Aargau Cancer League Krebsregister Aargau 2009: CHF 228,442. 2010: CHF 32,444. Beitrag an Konzeptarbeit zum Aufbau des Krebsregisters Künzler Alfred 2010: CHF 44,500. Externer Psychiatrischer Dienst, Kanton Aargau, Aarau/Baden Individualisierte psychoonkologische Psychotherapie: Inanspruchnahme, Inhalte und Evaluation des Therapieprozesses und der Ergebnisse 33 Recker Franz Kwiatkowski Maciej 2009: CHF 30,000. Klinik für Urologie, Kantonsspital Aarau, Aarau Erfassung der Prostata-Todesfälle im Kanton Aargau im Rahmen des Forschungsprogramms «Eine prospektive, randomisierte Studie zur aktiven Vorsorgeuntersuchung des Prostatakarzinoms für Männer zwischen 55 70 Jahren im Kanton Aargau» Basel Cancer League Bentires-Alj Mohamed 2010: CHF 140,000. Friedrich Miescher Institut für biomedizinische Forschung (FMI), Basel Role of the tyrosine phosphatase SHP2 in breast cancer Bubendorf Lukas Zlobec Inti 2009: CHF 63,940. Institut für Pathologie, Universitätsspital Basel, Basel Development of optimized criteria for EGFR status by fluorescence in situ hybridization in human carcinomas and application to cytology specimens Bubendorf Lukas 2010: CHF 50,000. Institut für Pathologie, Universitätsspital Basel, Basel Swiss Lung Pathology Working Group Lung Cancer Group SAKK (Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung) Urogenital Tumors Project Group SAKK New Technology Committee, International Academy of Cytology Evaluation von potenziellen Zielgenen innerhalb des 10q22-Amplikons beim Prostata- und Mammakarzinom Burger Bettina 2009: CHF 40,000. Departement Biomedizin, Universitätsspital Basel, Basel New approach for improvement of early diagnosis and prediction in familial adenomatous polyposis coli (FAP) by genetic analysis of skin involvement APC mutations and their influence to lesions of skin Christofori Gerhard 2010: CHF 170,000. Institut für Biochemie und Genetik, Universität Basel, Basel The role of mirnas in epithelial to mesenchymal transition (EMT) and cancer metastasis Fischer Claude 2010: CHF 30,000. Departement Otorhinolaryngologie, Universitätsspital Basel, Basel A new tumor issue based classification on head and neck squamous cell carcinoma according to HPV expression and cell cycle regulator proteins allows an individualized treatment modality choice for HPV positive and negative carcinomas Grüth Uwe Rochlitz Christoph 2009: CHF 30,000. Brustzentrum/Frauenklinik, Universitätsspital Basel, Basel Monika Eichholzer Institut für Sozial- und Präventivmedizin, Universität Zürich, Zürich Entwicklung von Übergewicht und Adipositas beim Mammakarzinom und ihre Bedeutung für Diagnose und klinisches Management

Heinimann Karl 2009: CHF 80,000. Departement Biomedizin, Universitätsspital Basel, Basel Identification of (epi)genetic alterations in colorectal cancers from hereditary non-polyposis colorectal cancer (HNPCC) patients Hess Christian Funk Georg A. 2009: CHF 60,000. Departement Forschung, Universitätsspital Basel, Basel In silico enhanced modelling to assess the risk for Epstein-Barr virus associated posttransplant lymphoproliferative disease (PTLD); a prospective cohort study Hynes Nancy Wodnar-Filipowicz Aleksandra 2010: CHF 50,000. Friedrich Miescher Institut für biomedizinische Forschung (FMI), Basel The involvement of bone marrow in breast carcinoma metastasis 34 Loeffler Sébastien 2009: CHF 104,880. Departement Biomedizin, Universitätsspital Basel, Basel The role of Shoca-2 in tumor development Mamot Christoph Wicki Andreas Rochlitz Christoph 2009: CHF 147,805. Klinik für Onkologie, Universitätsspital Basel, Basel Expanding immunoliposomal strategies towards vascular endothelial cells (VEGFR-2) and vascular endothelial tip cells (VEGFR-3) Moroni Christoph 2010: CHF 75,000. Departement Biochemie, Universität Basel, Basel Identification of «essential» genes in human leukemia cells as biomarkers and targets for intervention Müller Philipp 2010: CHF 39,800. Departement Biomedizin, Universitätsspital Basel, Basel Generation of cellular reporter systems to monitor the maturation and T-cell stimulatory capacity of dendritic cells upon treatment with anti-tumor therapeutics Nagamine Yoshikuni Bentires-Alj Mohamed 2009: CHF 82,800. Friedrich Miescher Institut für biomedizinische Forschung (FMI), Basel Roles of the DEAH helicase RHAU in RAS-dependent cancers Rentsch Cyrill A. 2010: CHF 30,000. Departement Urologie, Universitätsspital Basel, Basel Ruiz Christian Bubendorf Lukas Departement für Pathologie, Universität Basel, Basel Evaluation of nuclear receptor binding protein 1 (NRBP1) expression and function in prostate cancer Roth-Chiarello Michael 2009: CHF 80,000. Pulmonary Cell Research Laboratory, Departement Forschung, Universitätsspital Basel, Basel Reactivation of C/EBP- expression in pleural malignant mesothelioma in order to stop proliferation Schwaller Jürg 2009: CHF 25,000. Departement Biomedizin, Universitätsspital Basel, Basel Developing targeted therapeutic strategies for childhood acute leukemia Schwaller Jürg 2010: CHF 25,000.- Departement Biomedizin, Universitätsspital Basel, Basel HIV-cofactors as therapeutic targets for infant leukemia Tapia Coya Bubendorf Lukas Savic Spasenija 2010: CHF 20,000. Institut für Pathologie, Universitätsspital Basel, Basel ING4 silencing as a diagnostic marker in breast cancer Zanetti Dällenbach Rosanna Fabbro Thomas Obermann Ellen Rochlitz Christoph Tschudin Sibil Wight Edward 2010: CHF 25,000. Universitätsspital Basel, Basel Schöneberger Cora-Ann Maurice E. Müller-Institut für Strukturbiologie, Departement Biozentrum, Universität Basel, Basel Improving breast cancer diagnostics by novel sonographic techniques

Zippelius Alfred 2009: CHF 100,000. Departement Innere Medizin, Universitätsspital Basel, Basel Anti-tumor immunity upon treatment with chemotherapy and radiotherapy potential synergism with specific immunotherapy approaches Zlobec Inti Lugli Alessandro 2010: CHF 70,000. Institut für Pathologie, Universitätsspital Basel, Basel Investigation on possible intratumoral heterogeneity of K-RAS and B-RAF gene mutations in matched primary and metastatic colorectal cancer Bern Cancer League Angst Eliane 2010: CHF 50,000. Universitätsklinik für viszerale Chirurgie und Medizin, Inselspital Bern, Bern How does N-myc downstream regulated gene-1 affect the development, aggressiveness and host-tumor interaction of pancreatic cancer? 35 Christe Andreas 2010: CHF 70,000. Universitätsinstitut für diagnostische, interventionelle und pädiatrische Radiologie, Inselspital Bern, Bern Optimal low-dose levels in CHEST-computed-tomography (CT) for minimal patient radiation and unimpaired detection of lung nodules and nodule volume measurement Frese Steffen 2010: CHF 50,000. Departement für klinische Forschung, Universität Bern, Bern Transcriptional regulation of sensitization to TRIAL-induced apoptosis in lung cancer cells Hegyi Ivan 2010: CHF 50,000. Klinik für Dermatologie, Inselspital Bern, Bern Identification of novel diagnostic and predictive tumor biomarkers for oral squamous cell carcinoma (OSCC) Hunger Robert 2009: CHF 60,000. Klinik für Dermatologie, Inselspital Bern, Bern Immuntherapie von Patienten mit kutanem T-Zell-Lymphom mit Telomerase-spezifischen Peptiden Karoubi Golnaz 2009: CHF 90,000. Forschungsgruppe Thoraxchirurgie, Departement für klinische Forschung, Universität/Inselspital Bern, Bern Isolation and characterization of cancer stem cells from human lung adenocarcinoma Klaeser Bernd 2010: CHF 50,000. Universitätsklinik für Nuklearmedizin, Inselspital Bern, Bern A new concept for breast imaging: breast-pet with multi-parametic tumor characterization and visualization by integration of metabolical and morphological imaging modalities and voxel-wise kinetic modeling Kuehni Claudia 2009: CHF 34,000. Institut für Sozial- und Präventivmedizin, Universität Bern, Bern The impact of prediagnostic symptomatic interval on mortality in childhood acute lymphoblastic leukemia a cohort study Parmentier Laurent 2010: CHF 21,000. Departement für klinische Forschung, Universität Bern, Bern Secondary prevention of skin cancers and field concretization in organ-transplant-patients: open-label, comparative study evaluation of the impact of sequential mal-pdt Saar Bettina 2009: CHF 10,000.- Universitätsinstitut für diagnostische, interventionelle und pädiatrische Radiologie, Universität/Inselspital Bern, Bern Bern cohort study of patients with hepatocellular carcinoma Stickel Felix 2009: CHF 100,000.- Institut für klinische Pharmakologie und viszerale Forschung, Universität Bern, Bern Epithelial-to-mesenchymal transition in cholangiocarcinogenesis: functional role of V 6 integrin Stroka Deborah 2010: CHF 90,000. Departement für klinische Forschung, Universität Bern, Bern Targeting SIRT1 for the treatment of liver cancer

Tschan Mario 2009: CHF 60,000. Institut für Sozial- und Präventivmedizin, Universität Bern, Bern Characterization of micrornas with a role in the pathogenesis of acute myeloid leukemia Vassella Erik 2009: CHF 60,000. Institut für Pathologie, Universität Bern, Bern Role of tumor suppressor micrornas located at regions which are frequently deleted in oligodendrogliomas for their role in conferring chemo resistance, proliferation and differentiation of glioma tumors Zehnder Pascal 2010: CHF 40,000. Klinik für Urologie, Inselspital Bern, Bern Electrophysiological assessment of the male canine pelvic autonomic neural anatomy and translation to the perioperative human setting in the context of nerve-sparing radical cystectomy 36 Zimmer Yitzhak 2009: CHF 85,000. Departement für klinische Forschung, Universität Bern, Bern Role of KRAS mutations in the response of tumor cells with oncogenic MET expression to anti MET targeted therapy Geneva Cancer League Ansari Marc 2010: CHF 140,000. Unité d onco-hématologie, Hôpital des enfants, Genève La pharmacogénomic chez les enfants atteints de cancer Bridevaux Pierre-Olivier 2010: CHF 50,000. Service de pneumologie, Département de médecine interne, Hôpitaux universitaires de Genève (HUG), Genève Short-term pre-operative rehabilitation for patients with lung cancer: a randomized trial Clément Virginie Radovanovic Ivan Schatlo Bawarjan 2009: CHF 86,140. Service de neurochirurgie, Département des neurosciences cliniques, Hôpitaux universitaires de Genève (HUG), Genève Identification and characterization of biomarkers in human brain tumors and brain cancer-initiating cells Dietrich Pierre-Yves 2009: CHF 97,500. 2010: CHF 101,300. Service d oncologie, Département de médecine interne, Hôpitaux universitaires de Genève (HUG), Genève Identification of glioma specific antigens: a step towards the development of multi-peptide vaccine Dietrich Pierre-Yves 2009: CHF 177,540. Service d oncologie, Département de médecine interne, Hôpitaux universitaires de Genève (HUG), Genève Soutien financier pour «Achat d un cytomètre analyseur FACSCantoTMII» Dietrich Pierre-Yves 2009: CHF 25,000. Service d oncologie, Département de médecine interne, Hôpitaux universitaires de Genève (HUG), Genève Passweg Jakob Service d hématologie, Département de médecine interne, Hôpitaux universitaires de Genève (HUG), Genève Soutien extraordinaire en vue de la campagne de vaccination contre la grippe H1N1 Gumy Pause Fabienne 2009: CHF 20,000. 2010: CHF 60,000. Unité d onco-hématologie pédiatrique, Département de pédiatrie, Hôpitaux universitaires de Genève (HUG), Genève ATM gene analysis in neuroblastoma Kern Lise 2009: CHF 60,000. Service de médecine de laboratoire & Service de pédiatrie, Hôpitaux universitaires de Genève (HUG), Genève Contribution de l analyse de la méthylation du promoteur du gène MLH1 dans la stratégie de dépistage du syndrome de Lynch ou du syndrome du cancer colorectal héréditaire non polyposique (HNPCC) Kindler Vincent 2010: CHF 108,000. Service d hématologie, Département de médecine interne, Hôpitaux universitaires de Genève (HUG), Genève Immunomodulation of tumor cell growth by mesenchymal stromal cells: relevance of graft-versus host disease and graft-versus leukemia effect in patients reconstituted with allogenic hematopoietic stem cells

Kridel Robert 2010: CHF 100,000. Service d oncologie, Département de médecine interne, Hôpitaux universitaires de Genève (HUG), Genève Bourse de chercheur débutant «Ligue genevoise contre le cancer et Fondation Dr. Henri Dubois-Ferrière Dinu Lipatti» Mach Nicolas 2010: CHF 96,600. Service d oncologie, Département de médecine interne, Hôpitaux universitaires de Genève (HUG), Genève Développement d un nouveau concept de traitement anti-cancéreux combinant deux approches innovatives dans le domaine de l immunomodulation: thérapie cellulaire et bloquage de CTLA-4 Mathes Thomas Imhof Beat 2009: CHF 96,667. 2010: CHF 96,667. Service d hématologie, Département de médecine interne, Hôpitaux universitaires de Genève (HUG), Genève Role of junctional adhesion molecule C (JAM-C) in normal B cell differentiation and in the malignant proliferation of B-cells from lymphoproliferative syndromes Reith Walter 2009: CHF 43,900. 2010: CHF 43,900. Département de pathologie et d immunologie, Faculté de médecine, Centre médical universitaire (CMU), Genève Identification des fonctions cellulaires et gènes régulés par le microarn oncogénique, microarn-155 Rodriguez Yvan 2010: CHF 70,000. Département de génétique et évolution, Université de Genève, Genève Diagnostic olfactif des mélanomes Sappino André-Pascal 2009: CHF 120,000. 2010: CHF 100,000. Unité d oncogénétique et de prévention des cancers, Service d oncologie, Hôpitaux universitaires de Genève (HUG), Genève The ATM gene in carcinogenesis

Schick Ulrike 2010: CHF 100,000. Radio-oncologie, Département de médecine interne, Hôpitaux universitaires de Genève (HUG), Genève Bourse de chercheur débutant «Ligue genevoise contre le cancer et Fondation Dr Henri Dubois-Ferrière Dinu Lipatti» Walker Paul 2009: CHF 95,528. 2010: CHF 95,528. Service d hématologie, Département de médecine interne, Hôpitaux universitaires de Genève (HUG), Genève Reconnaissance d un antigène tumoral exprimé par les gliomes: le potentiel des cellules T de faible avidité pour l immunothérapie Grisons Cancer League 38 Buchli Christian 2009: CHF 15,000. 2010: CHF 15,000. Klinik für Chirurgie, Kantonsspital Graubünden, Chur Stipendium I und II zur Studie kolorektale Chirurgie/Rektumkarzinom Cathomas Richard Köberle Dieter Ruhstaller Thomas Mayer Gisela Räss Andrea Mey Ulrich von Moos Roger 2009: CHF 20,000. Departement für medizinische Onkologie, Kantonsspital Graubünden, Chur Oxaliplatin infusion in combination with capecitabine for metastatic colorectal carcinoma: can it reduce neuropathy? Cathomas Richard von Moos Roger 2009: CHF 15,000. Departement für medizinische Onkologie, Kantonsspital Graubünden, Chur Granatapfelstudie PSA-Bio-Studie: Randomisierte Phase-IIb-Doppelblindstudie zur Testung der Wirkung von natürlichem Fruchtgetränk auf den PSA-Wert von Prostatakarzinompatienten Neuchâtel Cancer League Registre neuchâtelois des tumeurs 2009: CHF 148,662. 2010: CHF 200,432. Beitrag an Krebsregister Schaffhausen Cancer League Egger Matthias 2009: CHF 25,000. 2010: CHF 25,000. Institut für Sozial- und Präventivmedizin, Universität Bern, Bern Stuck Andreas Geriatrische Abklärungsstation, Inselspital Bern, Bern Cancer epidemiology in older adults: population-based research of trends and factors associated with cancer mortality in Switzerland, 1990 2007 St Gallen-Appenzell Cancer League Burkhard Ludewig 2009: CHF 150,000. Institut für Immunbiologie, Kantonsspital St. Gallen, St. Gallen Multiepitop-Impfung von Grad III/IV Melanompatienten mit dendritischen Zellen: Bedeutung von Peptidaffinität und -dichte für die optimale Generierung von tumorspezifischen zytotoxischen T-Lymphozyten Krebsregister St. Gallen-Appenzell 2009: CHF 210,000. 2010: CHF 228,300. Beitrag an Krebsregister

Thurgau Cancer League Biotechnologie-Institut Thurgau (BITG) 2010: CHF 25,000. in Kreuzlingen und an der Universität Konstanz, Deutschland Beitrag an einen neuen Zellsorter für die anwendungsorientierte Grundlagenforschung zur Entstehung und Behandlung von Krebs Ticino Cancer League Carbone Giuseppina 2009: CHF 70,000. 2010: CHF 65,000. Laboratorio di oncologia sperimentale, Istituto oncologico della Svizzera italiana (IOSI), Bellinzona MicroRNA network regulated by ETS transcription factors in prostate cancer Frattini Milo 2009: CHF 55,000. 2010: CHF 50,000. Laboratorio di diagnostica molecolare, Istituto cantonale di patologia (ICP), Locarno Investigation of the role of NEU3 in colorectal carcinogenesis and in the prediction of efficacy of EGFR targeted therapies 39 Grassi Fabio 2009: CHF 50,000. 2010: CHF 40,000. Istituto di ricerca in biomedicina (IRB), Bellinzona Purinergic signaling in the pathophysiology of central nervous system infiltration in T-cell leukemia Molinari Francesca 2010: CHF 46,560. Laboratorio di diagnostica molecolare, Istituto cantonale di patologia (ICP), Locarno Characterization of Ras and BRAF mutations in GIST patients Napoli Sara 2009: CHF 70,000. Laboratorio di oncologia sperimentale, Istituto oncologico della Svizzera italiana (IOSI), Bellinzona Noncoding promoter-associated RNA and small RNA based transcriptional regulatory networks in cancer cells: mechanisms and therapeutic applications Thelen Marcus 2009: CHF 55,000. 2010: CHF 40,000. Istituto di ricerca in biomedicina (IRB), Bellinzona Detailed study of the interactions and subcellular distribution of the tumorigenic chemokine receptor CXCR7/RDC1 in lymphocytes Zurich Cancer League Arcaro Alexandre 2009: CHF 64,777. Klinik für Onkologie, Kinderspital Zürich, Universitäts-Kinderkliniken, Zürich Targeting P13K isoforms in human glioblastoma Arni Stephan Weder Walter 2010: CHF 64,668. Klinik für Thoraxchirurgie, UniversitätsSpital Zürich, Zürich Activity based protein profiling in human lung cancer biopsies Bergsträsser Eva 2009: CHF 51,048. Kompetenzzentrum für pädiatrische Palliative Care, Kinderspital Zürich, Zürich Kuehni Claudia E. Institut für Sozial- und Präventivmedizin, Universität Bern, Bern The Swiss childhood cancer survivor study: socio-economic outcomes in adulthood Bernasconi Michele Schäfer Beat 2009: CHF 63,777. 2010: CHF 67,668. Zentrum für klinische Forschung, Departement für pädiatrische Onkologie, Kinderspital Zürich, Zürich Development of targeting systems for improved drug delivery and imaging of pediatric soft tissue sarcomas based on tumor specific peptides Favrot Claude 2009: CHF 115,938. Klinik für Kleintiermedizin, Vetsuisse Fakultät, Universität Zürich, Zürich Characterization of newly discovered canine papillomavirus 3 (CBV3) and assessment of its carcinogenic potential

Felley-Bosco Emanuela 2009: CHF 59,874. Institut für molekulare Onkologie, UniversitätsSpital Zürich, Zürich Alterations in NF2 signaling pathway in malignant pleural mesothelioma Felley-Bosco Emanuela 2010: CHF 51,353. Institut für molekulare Onkologie, UniversitätsSpital Zürich, Zürich Sonic hedgehog signaling in malignant pleural mesothelioma Fontana Adriano Birchler Thomas 2009: CHF 60,828. Institut für experimentelle Immunologie, Universität Zürich, Zürich Is fatigue and tumor development in EBV infection due to clock gene dysfunction? 40 Gorr Thomas A. Vogel Johannes 2009: CHF 62,342. 2010: CHF 66,932. Institut für Veterinärphysiologie, Vetsuisse Fakultät, Universität Zürich, Zürich Chorio-allantoic membrane assay for preclinical cancer therapy screening: simultaneous targeting of tumor vasculature and the metabolic symbiosis between oxygenated and hypoxic tumor cells Grotzer Michael 2009: CHF 108,850. Klinik für Onkologie, Kinderspital Zürich, Universitäts-Kinderkliniken, Zürich Identification and validation of novel c-myc target genes in childhood medulloblastoma Heinzelmann Viola 2009: CHF 58,412. Institut für Frauenheilkunde und Gynäkologie, UniversitätsSpital Zürich, Zürich Wnt signaling in ovarian cancer SFRP4 and FGF9 as key regulators of the Wnt-Signaling pathway in ovarian cancer acronym: WOC-Study Hornung Rainer 2009: CHF 26,834. Psychologisches Institut, Universität Zürich, Zürich Parents caring for a child with a life-limiting illness: an assessment of individual and dyadic coping and personal growth Krek Wilhelm 2009: CHF 130,106. Institut für Zellbiologie, ETH Zürich, Zürich URI, a potential novel oncogene product in hepatocellular carcinoma Kristiansen Glen 2010: CHF 48,000. Institut für klinische Pathologie, Universität Zürich, Zürich Müntener Michael Klinik für Urologie, UniversitätsSpital Zürich, Zürich Funktionelle Analyse von CANT1 als neues Therapieziel und seine Eignung als diagnostischer Marker des Prostatakarzinoms Marra Giancarlo 2010: CHF 134,601. Institut für molekulare Krebsforschung, Universität Zürich, Zürich Functional characterization of KIAA1199: toward a novel biomarker of colorectal neoplasia Marti Thomas Felley-Bosco Emanuela Stahel Rolf A. 2009: CHF 73,212. Institut für molekulare Onkologie, UniversitätsSpital Zürich, Zürich Modulation of translesion synthesis: impact on chemotherapy resistance in malignant pleural mesothelioma Moch Holger Rechsteiner Markus 2009: CHF 100,000. Institut für klinische Pathologie, Universität Zürich, Zürich VHL mutation analyses for risk profiling of sporadic clear cell RCC Müller Anne 2009: CHF 55,828. 2010: CHF 59,932. Institut für molekulare Krebsforschung, Universität Zürich, Zürich Prevention of gastric cancer through the development of a Helicobacter vaccine Nadal David 2009: CHF 63,777. Klinik für Infektiologie, Kinderspital Zürich, Zürich TLR9 agonist cancer therapy is rather detrimental than beneficial in EBV-harboring tumors Riediger Thomas 2009: CHF 65,342. Institut für Veterinärphysiologie, Vetsuisse Fakultät, Universität Zürich, Zürich Blockade of the pro-inflammatory neuromodulator nitric oxide as a possible clinical approach to treat cancer anorexia

Weller Michael 2010: CHF 65,828. Klinik für Neurologie, UniversitätsSpital Zürich, Zürich Dehler Silvia Krebsregister des Kantons Zürich, Zürich Ohgaki Hiroko International agency for research on cancer (IARC), WHO, Lyon, France A population-based study on glioblastoma in the Canton of Zurich Wollscheid Bernd 2010: CHF 82,668. Institut für molekulare Systeme, ETH Zürich, Zürich Quantitative proteomic analysis of Hodgkin s and non-hodgkin s lymphoma plasma membrane glycoproteins Wüest Thomas Renner Christoph 2009: CHF 57,342. 2010: CHF 64,248. Klinik für Onkologie, UniversitätsSpital Zürich, Zürich Fuchs Bruno Muff Roman Forschungslabor Orthopädie, Klinik Balgrist, Zürich Sensitation of sarcomas for chemotherapy by tumor cell targeted TNF-Fusion 41 Zaugg Kathrin 2010: CHF 52,700. Klinik für Radio-Onkologie, UniversitätsSpital Zürich, Zürich Carnitine palmitoyltransferase 1C (CPT1C): a novel p53-dependent regulator of human cancer resistance against hypoxia

Programme research: Supporting translational and clinical research 42 Since 2003 the Foundation Cancer Research Switzerland (formerly Oncosuisse) has supported translational and clinical research with two funding programmes: Collaborative Cancer Research Projects (CCRP) and International Clinical Cancer Research Groups (ICP). The aim of both the CCRP and ICP is to support collaboration among different research disciplines and institutes at the national level and in the case of the ICP at the international level. Collaborative Cancer Research Projects (CCRP) Cancer research is a complex undertaking, especially due to the enormous advances in molecular genetics in recent decades. Today it is impossible for individual disciplines or research teams to have an overview of this complexity. Central questions can only be tackled with close cooperation among various specialist areas and institutes. And it often takes many years or decades until a discovery in the laboratory finally results in a clinical application for patients. International Clinical Cancer Research Groups (ICP) In contrast to basic research in Switzerland, which is among the world s best, clinical cancer research in this country is faced with a number of political, structural, and monetary difficulties. Over the last three decades, this has caused Swiss clinical research to drop down into the midfield in an international comparison. Supporting clinical research is therefore a pressing concern not only for the Swiss Cancer League and the Foundation Swiss Cancer Research. The ICP are clinical research groups in which researchers and physicians in several countries work together. These international research projects have their centres in Switzerland, which means that they are coordinated and managed from within Switzerland. A research group in the ICP programme receives funding of maximum CHF 200,000 per year, or a total of CHF 800,000 over the four years of the project duration. The CCRP are multidisciplinary research collaborations with a longer-term duration of five or more years. The focus is on supporting translational research studies that shorten the way from the laboratory to the hospital bed and thus seek to boost medical progress. The research projects are often complex and made up of several subprojects that are conducted at different institutes. The aim is for diverse specialists in research and medicine to pursue a common objective, exchange their ideas, expertise, and findings, and in this way to improve and accelerate the knowledge gain. Since the funding launch, total grants of CHF 14.7 million have been provided for programme research (in the period 2004 to 2010), of which CHF 10.1 million went to six CCRP and CHF 4.6 million went to seven ICP. The CCRP, which earmarked large funds, were discontinued in 2009 in favour of the better Kurt Bodenmüller Communications manager at the Scientific Office, Swiss Cancer League

manageable funding of individual projects. ICP calls for proposals are also no longer being announced. Instead, since 2009 funding has been given to clinical research institutions via research contracts and agreements (see here the article on research funding on page 6).

Collaborative Cancer Research Projects (CCRP) List of funded research projects Brisken Cathrin et al. CCRP OCS 01448-12-2003 CHF 1,750,000. Institut suisse de recherche expérimentale sur le cancer (ISREC), Faculté sciences de la vie, EPF de Lausanne, Lausanne The role of Wnt signalling in breast cancer 44 Hemmings Brian A. CCRP OCS 01613-12-2004 CHF 800,000. Friedrich Miescher Institut für biomedizinische Forschung (FMI), Basel Development of molecular strategies for therapeutic interference with glioblastomas Continuation of the project: Merlo Adrian et al. CCRP OCS 01613-12-2004 CHF 1,276,200. Neurochirurgische Klinik, Universitätsspital Basel, Basel Development of molecular strategies for therapeutic interference with glioblastomas Krek Wilhelm et al. CCRP OCS 01262-06-2002 CHF 1,684,900. Institut für Zellbiologie, ETH Zürich, Zürich Identification of molecular signatures of human prostate cancer and their validation in animal models and application in the clinics Rüegg Curzio et al. CCRP OCS 01812-12-2005 CHF 2,209,500. Division de pathologie expérimentale, Université de Fribourg, Fribourg Tumor-mediated mobilization of bone marrow cells: Implications in tumor angiogenesis, lymphangiogenesis and metastasis, and disease monitoring Sommer Lukas et al. CCRP OCS 01972-12-2006 CHF 1,898,500. Abteilung Zell- und Entwicklungsbiologie, Anatomisches Institut, Universität Zürich, Zürich Neural crest-derived cancer stem cells in melanoma and Merkel cell carcinoma: Their role in initiation, progression and therapeutic response The funded research projects in brief Brisken Cathrin et al. The role of Wnt signalling in breast cancer CCRP OCS 01445-12-2003 Duration: 01.07.2004 31.06.2009 CHF 1,750,000. Breast cancer affects one out of 8 women in Western countries. In Switzerland 1,300 women die each year of the disease. Over the past years, there has been an increase in targeted therapies. In contrast to traditional chemotherapies, these aim at interfering with specific molecular signals. Herceptin is one example of a drug that blocks a specific growth factor receptor (ErbB). In the course of this project we examined the role of the wnt signalling cascade in breast cancer development. Our aim was to provide biological insights for novel molecularbased therapeutic approaches. The wnt family comprises a number of signalling molecules that influence the development of colon cancer and melanoma. They bind to re- ceptors on the cell surface, which in turn send signals to the cell nucleus via the protein -catenin. This results in the activation of target genes and the synthesis of new proteins. We analyzed the role of this signalling cascade in the development of breast cancer and found that it has a role both early on as well as at later stages of the disease. Three groups with different expertise collaborated in this project: Using the mouse model, Cathrin Brisken s group demonstrated that the wnt signalling cascade is activated in the course of the hormonal cycle by the pregnancy hormone progesterone. Activation of wnt signalling results in cell proliferation. Together with pathologist Maryse Fiche, we analyzed breast epithelial and stromal cells from normal breast tissue and breast tumour samples and showed that activation of wnt signalling in normal human breast cells also results in increased cell proliferation. Nancy Hynes team examined the connection between wnt signalling and activation of the epidermal growth factor receptor EGFR/Erb1. That team showed that wnt signalling

enhances breast cancer cell motility a finding that has important implications at later stages of the disease when tumour cells infiltrate into surrounding tissue and metastasize. Prof. Dr Cathrin Brisken Swiss Institute for Experimental Cancer Research (ISREC) School of Life Sciences Swiss Federal Institute of Technology Lausanne (EPFL) NCCR Molecular Oncology SV2.832, Station 19 CH-1015 Lausanne Phone +41 (0)21 693 07 81 Fax +41 (0)21 693 07 40 cathrin.brisken@epfl.ch In collaboration with: Dr. Maryse Fiche, Institut universitaire de pathologie, CHUV, CH-1011 Lausanne Prof. Dr. Nancy Hynes, Friedrich Miescher Institute for Biomedical Research, CH-4058 Basel Hemmings Brian A. Development of molecular strategies for therapeutic interference with glioblastomas KFP OCS 01613-12-2004 Duration 01.01.2006 01.09.2011 CHF 2,076,200. Continuation of the project of Merlo Adrian et al. Neurochirurgische Klinik, Universitätsspital Basel, Basel Glioblastoma multiforme (GBM) is the most aggressive and lethal form of brain cancer, with a mean patient survival time of one year, with less than 10 % of patients surviving over five years. The high malignancy and low survival rates of GBM have been attributed to treatment resistance and invasion to the adjacent normal brain. Past experimental studies have identified protein kinases as potential therapeutic targets; however, the response rates of inhibitors of PDGF, VEGF and EGF receptors (overexpressed in GBM) have been somewhat disappointing in clinical studies. Therefore, there is currently a desperate need to identify the molecular mechanisms of therapy resistance and driving kinases which might be the Achilles heel of GBM. In a search for novel molecular targets, our kinome-focused microarray analysis identified overexpressed protein kinase expression in fresh brain tumours including primary and secondary glioblastoma, astrocytoma and oligodendroglioma. The study identified targets that have been previously associated with gliomagenesis (e.g. EGFR or PDGFR), as well as novel kinases that have not been previously reported in GBM. Our recent work has focused on the most promising novel targets that were highly overexpressed and activated in human gliomas. MAP kinase-interacting kinase 1 (MNK1) was highly expressed in GBM compared to normal brain, and its elevated protein level was confirmed in primary GBMs and in glioma cell lines. Targeting MNK1 activity together with rapamycin induced cell cycle arrest and strongly inhibited global translation and GBM cell proliferation. Furthermore, MNK1-signalling converged with TGF- pathways and regulated glioma cell motility, identifying MNK1 pathway as an attractive point for therapeutic intervention. TAM family of receptor tyrosine kinases (TAM-TKs) was shown to be overexpressed in gliomas and promoted survival in vitro upon etoposide treatment independent of PI3K/PKB and MAPK signalling. TAM-TK may thus mediate GBM resistance to therapy, which is a major obstacle in GBM treatment. Two other tyrosine kinases and their upstream receptors that are found normally only in haematopoietic cells were highly overexpressed in brain tumour samples, GBM cell lines and cancer spheres. Strikingly, treatment with two specific small molecule inhibitors strongly blocked basal and EGFR (hyperactivated in the most of GBMs) mediated proliferation and migration of GBM cells. Due to the known driving roles of these kinases, we will further investigate their role in GBM animal models to establish optimal therapeutic interference. Our study has analyzed signalling networks and has been the platform to establish the potential of identified deregulated pathways for development of novel targeted thera pies, as well as diagnostics and prognostic markers for gliomas. If our in vitro results are reflected in in vivo animal models, then inhibition of these kinases could be in fact novel therapeutic treatments that will ultimately improve the life quality of brain cancer patients. Dr. Brian A. Hemmings Friedrich Miescher Institut für biomedizinische Forschung (FMI) Maulbeerstrasse 66 CH-4058 Basel Phone +41 (0)61 697 48 72 Fax +41 (0)61 697 39 76 brian.hemmings@fmi.ch Krek Wilhelm et al. Identification of molecular signatures of human prostate cancer and their validation in animal models and application in the clinics KFP OCS 01262-06-2002 Duration: 01.04.2008 01.04.2010 CHF 684,900. Prostate cancer is a frequent cause of death among men in Western countries. The causes underlying the development of prostate cancer are still incompletely defined. There are several risk factors contributing to prostate cancer development, including the environment, lifestyle and genetic predisposition. At early stages, prostate cancer is asymptomatic. However, as it progresses, it can take on aggressive behaviour leading ultimately to metastasis. It would therefore be highly desirable to define highly sensitive and specific molecular biomarkers that allow precise early diagnosis of prostate cancer, an accurate prognosis of the disease and predictions as to the response to specific therapies. In this project, researchers from different disciplines ranging from cancer biology and pathology to proteomics, computer sciences and clinical oncology collaborated to develop innovative strategies for the discovery of novel biomarker signatures for prostate cancer. The starting point of this project was the PTEN tumour suppressor gene, which is functionally inactivated in about 60 % of human prostate cancer patients. The loss of PTEN function in 45

prostate epithelial cells leads to uncontrolled cell proliferation. In the first step of the new strategy, the PTEN gene was inactivated in the mouse in a prostate-specific manner, resulting in the development of prostate cancer in the mouse. Through the application of high-throughput proteomic analysis, hundreds of prostate-specific cell surface proteins were then identified and catalogued. The comparison of the protein data sets derived from healthy prostate tissue and prostate cancer tissue of the mouse then allowed the identification of a protein signature typical for the mutant version of PTEN and hence also prostate cancer. The second step of the strategy encompassed the validation of this new biomarker signature in tissue and serum samples of prostate cancer patients. This involved a comparative analysis of the identified signature in prostate cancer patients and control groups. Importantly, this work allowed the identification of a serum biomarker signature for the accurate diagnosis of prostate cancer in man. These new biomarkers must now be further tested and validated in larger clinical studies for their utility as a new suitable diagnostic test. Prof. Dr. Wilhelm Krek Institut für Zellbiologie ETH Hönggerberg HPM F42 CH-8093 Zürich Phone +41 (0)44 633 34 47 Fax +41 (0)44 633 13 57 wilhelm.krek@cell.biol.ethz.ch In collaboration with: Prof. Dr. Rudolf Aebersold, ETH Zürich, Institute of Molecular Systems Biology, CH-8093 Zürich Prof. Dr. Thomas Cerny, Fachbereich Onkologie/ Hämatologie, Dept. Innere Medizin, Kantonsspital, CH-9007 St. Gallen Dr. Silke Gillessen, Kantonsspital, CH-9007 St. Gallen Prof. Dr. Holger Moch, Universitätsspital Zürich, Institut für klinische Pathologie, CH-8091 Zürich The strategy developed within this project represents an important next step for the development and application of serum biomarkers that make it possible to predict the presence of prostate cancer with high precision, stability and reproducibility. This progress was only possible through an interdisciplinary research effort involving cancer biologists, proteomic experts, pathologists, computational scientists and clinical oncologists.

Rüegg Curzio et al. Tumor-mediated mobilization of bone marrow cells: Implications in tumor angiogenesis, lymphangiogenesis and metastasis, and disease monitoring KFP OCS 01812-12-2005 Duration: 01.11.2006 01.11.2011 CHF 2,209,500. Whereas localized cancer can be cured with a good success rate nowadays, metastatic, advanced cancers remain difficult to cure. The ability to detect and interfere with invasion and metastasis may open up new diagnostic, prognostic and therapeutic opportunities. The formation of tumour vasculature (i.e. tumour angiogenesis) is an important event contributing to tumour growth and metastasis. Since 2004 a treatment inhibiting the formation of tumour blood vessels has been in use in the clinic and prolongs survival of patients with metastatic cancers. In spite of this success, many important questions remain open on the use of anti-angiogenic drugs in patients, in particular how to assess angiogenesis, how to improve the use of these drugs and how to detect early events leading to metastasis. For example, bone marrow-derived cells are attracted to tumour sites to promote tumour angiogenesis, invasion and metastasis by releasing many growth factors, but the mechanisms involved are not fully understood. Goal The first goal of this project is to identify mechanisms by which bone marrow-derived cells promote tumour progression and metastasis as a basis for the development of novel therapeutic approaches to suppress metastasis. The second goal is to use these cells as indicators of tumour angiogenesis and metastatic spreading for early diagnosis and monitoring of cancer progression and therapy. Methods To address these questions we will combine molecular, cellular, and animal experiments with clinical studies. In animal studies we will use mouse tumour models to follow up the effect of the growing tumour on the mobilization of bone marrow-derived cells and of therapeutic interventions. Animal experiments are still necessary to study angiogenesis and metastasis, but whenever possible we will use substitution experiments in culture. In culture experiments we will study changes in function of these cells, and with molecular biology experiments and genetic experiments we will modify cells or mice to validate mechanisms. Analysis in patients will be limited to blood samples. Results We have obtained novel insights into the possible use of circulating bone marrow-derived cells for the monitoring of angiogenesis and have uncovered new potential therapeutic targets. Specifically we have: identified novel circulating bone marrow-derived cells as candidate biomarkers of angiogenesis; described a novel mechanism by which tumours instruct bone marrow progenitor cells to acquire pro-angiogenic properties; completed a clinical study aimed at validating preclinical results; characterized the role of two endothelial cell molecules in angiogenesis and shown that their inhibition suppresses tumour growth. Benefits for patients The results obtained in this project have three potential implications: Prognosis/prediction: Results may allow the identification of patients at risk of developing metastases, which would be treated accordingly. Obtained results will help to design new clinical studies. Monitoring: Detected parameters may be used to monitor patients during therapy to evaluate treatment efficacy. New clinical studies are currently being planned. Therapy: Tools generated by this project may translate into new therapeutic approaches to suppress tumour spreading to lymph nodes and to distant sites. Drug development is beyond the scope of this application. However, if some of the tools developed in preclinical experiments appear particularly promising, we will establish appropriate collaborations with biotech or pharmaceutical companies. Prof. Dr Curzio Rüegg Department of Medicine Faculty of Science University of Fribourg 1, rue Albert-Gockel CH-1700 Fribourg Phone +41 (0)26 300 87 66 Fax +41 (0)26 300 97 33 curzio.ruegg@unifr.ch In collaboration with: Prof. Dr. Gerhard Christofori, Institut für Biochemie und Genetik, Departement Biomedizin, Universität Basel, Mattenstrasse 28, CH-4058 Basel Prof. Dr. Beat A. Imhof, Département de pathologie et immunologie, Faculté de médecine, Centre médical universitaire (CMU), Université de Genève, rue Michel-Servet 1, CH-1211 Genève Prof. Dr. Christoph Rochlitz, Departement Biomedizin, Universität Basel, CH-4031 Basel Prof. Dr. Cristiana Sessa, Istituto oncologico della Svizzera italiana (IOSI), Ospedale San Giovanni, CH-6500 Bellinzona Prof. Dr. Roger Stupp, Multidisciplinary Oncology Center, Centre hospitalier universitaire vaudois (CHUV), CH-1011 Lausanne Sommer Lukas et al. Neural crest-derived cancer stem cells in melanoma and Merkel cell carcinoma: Their role in initiation, progression and therapeutic response CCRP OCS 01972-12-2006 Duration: 01.01.2008 31.12.2012 CHF 1,898,500. Cancer stem cells represent an emerging field for cancer research because of the increasing evidence that these cells have the capacity to sustain tumour formation and regeneration. Similar to normal stem cells, cancer stem cells display self-renewing capacity and have the potential to differentiate to a certain extent. Normally, tissue-specific stem cells are implicated in the generation, homeostasis and regeneration of particular organs. In analogy, 47

the cancer stem cell concept predicts that particular cancers arise from specific cancer stem cell types. Unfortunately, cancer stem cells appear to be relatively resistant to radiotherapy and chemotherapy. Thus, it is imperative to better characterize cancer stem cells in order to establish novel therapies specifically targeting these cells. 48 The skin is the organ with the highest incidence of malignancies, and skin cancers occur more frequently than all other cancers combined. Of the various skin cancers, melanoma is responsible for most deaths. Melanoma cells arise by malignant transformation of melanocytes, the pigment cells in our skin. These cells, in turn, originate during development in the neural crest. In accordance with the hypothesis that melanoma might develop from cancer stem cells, we have identified melanoma stem cells with features of neural crest stem cells. These cells are responsible for both tumour initiation and tumour maintenance. Intriguingly, we found that melanoma stem cells appear to have specific capacities to evade anti-cancer immune responses. Based on our findings, we will investigate the specific genetic properties and growth requirements of melanoma stem cells with the goal of establishing novel targets for the elimination of cancer stem cells. Indeed, we have already identified chemical substances that counteract melanoma stem cell growth and tumour formation in animal models. Our study highlights the importance of collaborative efforts involving stem cell biologists, pathologists, and pharmacologists for cancer stem cell research and the development of new treatment strategies. Prof. Dr. Lukas Sommer Anatomisches Institut Zell- und Entwicklungsbiologie Universität Zürich Winterthurerstrasse 190 CH-8057 Zürich Phone +41 (0)44 635 53 50/54 43 Fax +41 (0)44 635 68 95 lukas.sommer@anatom.uzh.ch In collaboration with: Prof. Dr. Michael Detmar, ETH Zürich, Institute of Pharmaceutical Sciences, CH-8093 Zürich Prof. Dr. Reinhard Dummer, Universitätsspital Zürich, Dermatologische Klinik, CH-8091 Zürich Dr. Daniela Mihic-Probst, Universitätsspital Zürich, Dept. Pathologie, CH-8091 Zürich

International Clinical Cancer Research Groups (ICP) List of funded research groups Ammann Roland A. et al. ICP OCS 02061-03-2007 CHF 118,000. Departement Hämatologie/Onkologie, Medizinische Universitäts-Kinderklinik, Inselspital, Bern International childhood liver tumour consortium research strategy for treatment and evaluation of hepatoblastoma and hepatocellular carcinoma Franceschi Silvia et al. ICP OCS 01355-03-2003 CHF 500,000. Groupe épidémiologie des infections et cancer, Centre international de recherche sur le cancer (CIRC), Lyon, France Risk of cancer in persons infected with HIV 49 Maibach Rudolf ICP OCS 01688-03-2005 CHF 791,510. International Breast Cancer Study Group (IBCSG), Coordinating Center, Bern Academic research activity of the International Breast Cancer Study Group (IBCSG) Sessa Cristiana et al. ICP OCS 01687-03-2005 CHF 800,500. Istituto oncologico della Svizzera italiana (IOSI), Ospedale San Giovanni, Bellinzona Towards an independent and efficient anticancer drug development in Switzerland: Potentiation of the Swiss SENDO Unit Zucca Emanuele et al. ICP OCS 01356-03-2003 CHF 983,000. Istituto oncologico della Svizzera italiana (IOSI), Ospedale San Giovanni, Bellinzona International Extranodal Lymphoma Study Group (IELSG): A network for improving the understanding and the clinical management of non-hodgkin s lymphomas arising at extranodal sites

The funded research groups in brief 50 Ammann Roland A. et al. International childhood liver tumour consortium research strategy for treatment and evaluation of hepatoblastoma and hepatocellular carcinoma ICP OCS 02061-03-2007 Duration: 01.07.2007 30.06.2011 CHF 118,000. Malignant liver tumours in children are extremely rare. Treatment results have improved considerably in the last 15 years. It has therefore become quite a challenge for treating physicians to choose the correct approach in this rapidly changing field. The Epithelial Liver Tumour Study Group of the International Society of Paediatric Oncology (SIOP) known as SIOPEL has contributed substantially to progress through their programme of clinical studies for treatment of childhood liver cancer. SIOPEL recently joined forces with the US Children s Oncology Group in a project called CHIC (Childhood Hepatic Tumours International Collaboration). Since 1990 clinical trials to optimize the treatment of hepatoblastoma and hepatocellular carcinoma have been and are continuing to be launched. Both more rational chemotherapy and improvements in surgical techniques have led to the better results. In these very rare tumours this was only possible by multidisciplinary international cooperation. In the case of SIOPEL, over 100 centres from 32 countries have participated in SIOPEL trials and studies. In the first two trials the concept of preoperative chemotherapy was introduced and adapted according to two groups with different prognosis. In the third trial it was proven that for the group with the better overall prognosis the chemotherapy can be reduced to a single agent, thus reducing the potential for possible serious toxicity to the kidneys and the heart function while achieving an excellent long-term result. The next trial generation is now focusing on optimizing an aggressive chemotherapy for patients at high risk of relapse, and on reducing the hearing impairment caused by single agent chemotherapy in standard risk patients. In the context of surgery, liver transplantation has taken on a greater role. An Internet-based worldwide registry for these interventions (Pediatric Liver Unresectable Tumour Observatory, PLUTO) has been set up. Besides treatment optimization, the group is further investigating molecular biological characteristics and other scientific parameters to be able to include these into better defined risk groups. The coordination of all these activities is carried out by Clinical Trials Unit at the Cancer Research UK in Birmingham, England, and by the trial committees. The statistical support is provided by the Coordinating Center of the International Breast Cancer Study Group (IBCSG) (R. Maibach). The Swiss Paediatric Oncology Group (SPOG) conducts the trials in Switzerland. The laboratory of the University Children s Hospital Zurich (M. Grotzer) collects the tissue samples for scientific investigation. PD Dr. Roland A. Ammann Departement Hämatologie/Onkologie Medizinische Universitäts-Kinderklinik Inselspital CH-3010 Bern Phone + 41(0)31 632 93 72 Fax + 41(0)31 632 95 07 roland.ammann@insel.ch In collaboration with: PD Dr. Michael Grotzer, Kinderspital Zürich, Onkologie/Neuroonkologie, CH-8032 Zürich Dr. Rudolf Maibach, International Breast Cancer Study Group (IBCSG), Coordinating Center, CH-3008 Bern Dr. Jack Plaschkes, Inselspital, University Children s Hospital, Dept. of Pediatric Surgery, CH-3010 Bern Prof. Dr. Arthur Zimmermann, Universität Bern, Institut für Pathologie, CH-3010 Bern Franceschi Silvia et al. Risk of cancer in persons infected with HIV ICP OCS 01355-03-2003 Duration: 01.01.2004 1.1.2009 CHF 500,000. Persons infected with HIV (PHIV) are at particular risk for many infection-related cancers due to the negative effect of immunosuppression on the outcome of co-infection with carcinogenic viruses. Objectives This collaborative project of the International Agency for Research on Cancer (IARC), the Swiss HIV Cohort Study (SHCS) and Swiss cantonal cancer registries (CRs) was initiated with the broad aim to improve knowledge on the causes and strength of the risk of cancer in PHIV in Switzerland. Methods The SHCS is a collaboration of seven centres throughout Switzerland that has enrolled over 15,000 PHIV since 1988. Over the same time period, CRs in six of these seven regions have been recording comprehensive quality-checked epidemiological data on cancer incidence. First in 2003, and again in 2007, patient records were linked between the SHCS and CRs, using specifically developed software to ensure confidentiality and resulting in an anonymous dataset of cancer diagnoses and mortality in the SHCS. Cancers identified through linkage were used to estimate incidence rates in the SHCS and to compare them with expected numbers of cancers from the general CR population. Study Results 1. Quantification of excess cancer risk in the SHCS in comparison to the general Swiss population (Clifford, Journal of the National Cancer Institute 2005; Franceschi, British Journal of Cancer 2010): In addition to the AIDS-defining cancers Kaposi sarcoma (KS), non-hodgkin lymphoma (NHL) and cervical cancer, significantly elevated risks

in PHIV were shown for Hodgkin s lymphoma (HL), nonmelanoma skin cancer and cancers of the anus, liver, lip/ mouth/pharynx and trachea/lung. 2. Time trends and risk factors for cancer incidence within the SHCS (Polesel, AIDS 2008; Franceschi, British Journal of Cancer 2008; Clifford, Blood 2009): The incidence of NHL (particularly primary brain lymphoma) and KS were confirmed to have greatly decreased in the combination antiretroviral therapy (cart) era. This beneficial effect remains strong up to 10 years after cart initiation. HL risk, on the other hand, does not appear to have changed over time or to have been significantly affected by cart. 3. Nested case-control studies of cancer aetiology (Franceschi, British Journal of Cancer 2006; Clifford, AIDS 2008): Frequent co-infection with HCV/HBV means that the direct effect of HIV-related immunodeficiency on hepatocellular carcinoma (HCC) has proven difficult to elucidate. Nevertheless, we showed a significant association between lower CD4 + cell counts and HCC risk, which was particularly evident for HBV-related HCC arising in non-intravenous drug users. 4. Sero-epidemiological studies (Sullivan, AIDS 2010): cart increases KS herpesvirus-specific humoral immune response and clearance of viremia among PHIV, consistent with the dramatic protection offered against KS. Recommendations Improving survival means that PHIV live long enough for the most severe long-term sequelae of carcinogenic viruses to manifest as non-aids-defining cancers (NADCs). Thus, NADCs can be expected to become an increasingly important complication of long-term HIV infection, and better cancer prevention strategies (control of immunosuppression, cervical cancer screening, control of hepatitis viral infections, smoking cessation) are a priority. Dr Silvia Franceschi Infections and Cancer Epidemiology Group International Agency for Research on Cancer (IARC) 150, cours Albert Thomas F-69372 Lyon Cedex 08 France Phone +33 472 73 84 02 Fax +33 472 73 8345 franceschi@iarc.fr In collaboration with: Prof. Dr. Christine Bouchardy, Registre genevois des tumeurs, Bd. de la Cluse 55, CH-1205 Genève Prof. Dr. Fabio Levi, Institut universitaire de médecine sociale et préventive, Université de Lausanne, rue du Bugnon 17, CH-1005 Lausanne Dr. Martin Rickenbach, Swiss HIV Cohort Study, CHUV, Mont-Paisible 16, CH-1011 Lausanne Dr. Luigi Del Maso, Servizio di Epidemiologia e Biostatistica, via Pedemontana Occ 12, I-33081 Aviano, Italia Maibach Rudolf Academic research activity of the International Breast Cancer Study Group (IBCSG) ICP OCS 01688-03-2005 Duration: 01.07.2005 01.07.2009 CHF 791,510. The International Breast Cancer Study Group (IBCSG) is a cooperative group that has conducted high quality and important clinical trials of adjuvant therapy for patients with operable breast cancer for the past 30 years. With its network of investigators spanning five continents, the IBCSG is dedicated to designing and conducting relevant trials, evaluating primary and secondary study results and presenting and publishing its findings in the best journals and at scientific congresses. IBCSG has been supported by Cancer Research Switzerland (and formerly by Oncosuisse) in the conduct of a series of studies, some of which have been completed and evaluated. The following results are only a selection of IBCSG s research activities: In two studies for pre- and postmenopausal patients conducted in the 1990s, IBCSG evaluated breast cancer treatment with chemotherapy and hormonal therapy. The IBCSG Tissue Bank serves as repository for tumour material from many of these patients. The IBCSG Pathology Review Office has now evaluated in 2,754 patients the role of peritumoural vascular invasion (PVI) for long-term outcome. It could be shown that this invasion is associated with larger and more aggressive tumours but does not have a negative impact on the prognosis of the patient if she has received adequate hormonal therapy. Nevertheless, the determination of PVI should be done to inform choice of the best therapy for the patient. In two other studies with a median observation time of 13 years, we analyzed the influence of the extent of oestrogen receptor expression on the efficacy of the chemotherapy given in combination with the hormonal treatment. High oestrogen receptor expression allows good efficacy of the hormonal therapy, thus reducing the impact of chemotherapy on the success of the treatment. Therefore, oestrogen receptor expression is an important factor in the choice of the optimal therapy. Chemotherapy also has a direct influence on the hormonal situation of the patient by reducing or completely stopping the ovaries from producing hormones. In a study of high-dose chemotherapy for patients with a high risk of relapse, the highest treatment effect was observed in the group of patients whose tumours carried oestrogen receptors. This leads to the hypothesis that even high-risk patients may benefit from hormonal therapy if the tumour shows a sufficient quantity of receptors. In the same study, the quality of life of the patients was assessed repeatedly by questionnaires. The quality of life indicators were combined with the relatively high toxicity experienced by the patients and the long-term outcome of the treatment to produce quality-adjusted time without symptoms and toxicity (Q-TWiST). Although the quality of life of the patients subjected to high-dose chemotherapy was lower during the treatment, they had a longer Q-TWiST. It may therefore be worthwhile to accept a short-term reduction of the quality of life by a burdensome chemotherapy if it is compensated by long-term treatment success. 51

52 Dr. Rudolf Maibach International Breast Cancer Study Group (IBCSG) IBCSG Coordinating Center Effingerstr. 40 CH-3008 Bern Phone +41 (0)31 389 91 96 Fax +41 (0)31 389 92 39 rudolf.maibach@ibcsg.org Sessa Cristiana et al. Towards an independent and efficient anticancer drug development in Switzerland: Potentiation of the Swiss SENDO Unit ICP OCS 01687-03-2005 Duration: 01.01.2006 31.12.2010 CHF 800,500. The clinical activities of the Swiss SENDO Unit (called SAKK/SENDO because of the close collaboration with SAKK) started in May 2006 with the activation of the first phase I study, preceded by the implementation of the collaborative network among participating centres. Overall, seven studies have been activated, and 189 patients were entered by December 2010. Patient accrual and the number of participating centres and ongoing studies increased up to 2009, with a decrease of patient accrual in 2010 due to the logistics of the studies. The aim of the Swiss SENDO Unit is to establish central coordination of phase I and II studies in Switzerland and to ensure closer interaction among centres, investigators and the SAKK collaborative group. The coordinating centre of the Swiss SENDO Unit is at the Istituto oncologico della Svizzera italiana (IOSI) in Bellinzona. There are now five active members: IOSI, Kantonsspital St. Gallen, CHUV Lausanne, Kantonsspital Basel and Kantonsspital Graubünden. Among seven studies activated (one phase II, six phase I of which three Ib and three first in human) four were completed by December 2010, and three are still ongoing. Completed studies: 1. SAT1-05-06: was started in May 2006 and closed in December 2007. Four centres participated, and 37 patients were recruited. The schedule of administration of satraplatin (a novel oral platinum compound) and capecitabine was assessed in adult patients with advanced solid tumours (open label phase Ib study). The results are reported in a full paper that has been accepted for publication. 2. SO43VELCO2: An open label phase II study of biweekly VELCADE TM and intermittent CAELYX TM in patients with ovarian cancer failing platinum containing regimens: two centres in Switzerland and five in Italy, 58 patients enrolled, activated in May 2006 and closed in January 2009. 3. SO65APOX01: First in human phase I dose finding and pharmacokinetic study of intravenous APO010, a recombinant form of human Fas ligand, in patients with solid tumours: two centres in Switzerland, 25 patients enrolled, activated in February 2007 and closed in January 2010. 4. SKSD00701: A phase Ib dose-finding study of satraplatin in combination with oral vinorelbine in patients with advanced solid tumours: two centres in Switzerland, 27 patients enrolled, activated in December 2007 and accrual closed in April 2010. The three ongoing studies are: 1. ST1968-DM-06-001: A phase I dose finding and pharmacokinetic study of intravenous camptothecin ST1968 in patients with solid tumours: two centres in Switzerland, 62 patients enrolled, activated in June 2007. 2. SKSD00702: A phase Ib study of the histone deacetylase inhibitor panobinostat (LBH589) given orally in combination with carboplatin and paclitaxel in patients with advanced solid tumours: three centres in Switzerland, 33 patients enrolled, activated in May 2008. 3. ST1968-DM-09-001: Phase I dose finding and pharmacokinetic study of daily administrations of the intravenous camptothecin namitecan (ST1968) in patients with refractory or recurrent solid tumours: two centres in Switzerland and one in Italy, 15 patients enrolled, activated in January 2010. The advantages of this network are that the investigators can have direct experience with the new compounds, they are accustomed to collaborating, and they are interested in continuing to work with the same drugs in phase II studies. This has been already proven by the positive findings achieved so far. Public opinion has become more aware of the need for and the importance of the development of anti-cancer drugs and, more generally, the importance of clinical research in Switzerland. In 2010 the number of new studies and patients enrolled decreased due to financial constraints of drug companies, the limited drug market in Switzerland as compared to other European countries, and competition with big European referral centres for phase I. The availability of the Swiss Sendo Unit allows the network to propose and implement innovative studies with limited financial support by drug companies but with greater scientific independence. Prof. Dr. Cristiana Sessa Istituto oncologico della Svizzera italiana (IOSI) Ospedale San Giovanni CH-6500 Bellinzona Phone +41 (0) 91 811 81 81 Fax +41 (0) 91 811 90 44 cristiana.sessa@eoc.ch In collaboration with: Prof. Dr. Franco Cavalli, Medical Oncology, IOSI, Ospedale San Giovanni, CH-6500 Bellinzona Prof. Dr. Thomas Cerny, Fachbereich Onkologie/ Hämatologie, Departement Innere Medizin, Kantonsspital, CH-9007 St. Gallen Prof. Dr. Richard Herrmann, Klinik für medizinische Onkologie, Kantonsspital, CH-4031 Basel Prof. Dr. Serge Leyvraz, Service d oncologie, Centre hospitalier universitaire vaudois (CHUV), CH-1011 Lausanne Dr. Roger von Moos, Kantonsspital Graubünden, CH-7000 Chur

Zucca Emanuele et al. International Extranodal Lymphoma Study Group (IELSG): A network for improving the understanding and the clinical management of non-hodgkin s lymphomas arising at extranodal sites ICP OCS 01356-03-2003 Duration: 01.01.2004 31.12.2011 CHF 983,000. Extranodal lymphomas represent approximately 30 40 % of all non-hodgkin s lymphomas, and their incidence is increasing. These lymphomas can develop from all organs and sites of the body, and their clinical history varies significantly depending on the organ of origin. Given the relative low frequency of cases per particular body site, no single institution worldwide would be ever able to accumulate enough cases in order to study the respective clinical history and to establish specific treatment strategies. The Oncology Institute of Southern Switzerland (IOSI) has been actively involved in this field in the last two decades. Twelve years ago, we decided to create the International Extranodal Lymphoma Study Group (IELSG) with the operational office located at the IOSI in Bellinzona. The IELSG is an international cooperative group of institutions that collaborate to perform studies in patients with extranodal lymphomas. The establishment of this group allowed collection of clinical data and biological material of several thousands of extranodal lymphoma cases. Thanks to this unique worldwide work, the group has performed more than 30 studies, many of which have been published (see www.ielsg.org). Several other studies are currently ongoing or planned. Originally, the IELSG conducted retrospective studies, but now the group is mainly engaged in prospective trials. Of the most recent contributions of IELSG, the conclusion of two important clinical studies is noteworthy. The IELSG 20 study was the first randomised trial of chemotherapy for primitive lymphoma of the brain to be completed. The study (published in The Lancet) allowed us to document that the combination of two drugs (cytarabine and methotrexate) when given at high doses represents the most efficient chemotherapeutic approach for this particular disease. Based on these results, we started the IELSG 32 study, which is currently ongoing and exploring the impact of stem cell transplantation on the survival of patients affected by this severe form of lymphoma. Another important recent achievement is the conclusion of the IELSG 19 randomised study, which showed the superiority of the combination of chlorambucil (a chemotherapeutic drug) and rituximab (a monoclonal antibody targeting the B-cells) as compared to treatment with chemotherapy alone in extranodal marginal zone lymphomas. The results of this study were presented to the scientific community at the most recent congress of the American Hematology Association in December 2010. In 2010 we also completed the accrual of a study aimed at evaluating the role of 18-FDG-PET scanning in the management of the primary mediastinal lymphoma. The results of this study will be presented to the scientific community at the 11th International Conference on Malignant Lymphoma in Lugano in June 2011. PD Dr. Emanuele Zucca Oncology Institute of Southern Switzerland (IOSI) Ospedale San Giovanni CH-6500 Bellinzona Phone + 41 (0)91 811 90 40 Fax + 41 (0)91 811 91 82 ielsg@ticino.com In collaboration with: Prof. Dr. Franco Cavalli, Istituto oncologico della Svizzera italiana, Ospedale San Giovanni, CH-6500 Bellinzona Dr. Mary Gospodarowicz, Ontario Cancer Institute, Princess Margaret Hospital, Dept. of Radiation Oncology, Toronto Ontario, Canada Prof. Dr. Emilio Montserrat, Clinic Hospital Universitari, Servicio de Hematologia, E-08036 Barcelona, España 53

54

Basic biomedical research 55 Cancer stem cells: The origin of cancer? Although there have been great medical advances in fighting cancer over the past few years, we are often rather powerless in the face of this disease. A better understanding of how different types of cancer develop and spread throughout the body could pave the way towards new forms of therapy. Up to now, it has been assumed that tumours are composed of a group of cells that multiply malignantly and thus contribute to tumour growth. According to a new hypothesis, however, cancer could also arise from individual cancer stem cells, which have a different growth and spreading potential than most of the tumour cells. Efficient treatment of tumours must therefore deal mainly with these cancer stem cells. During embryonic development, normal stem cells are responsible for building organs, and in the adult body they contribute towards maintenance and regeneration of tissues and organs. They can perform these functions thanks to their ability to multiply almost indefinitely and to develop into different cell types in the body. There are many indications that cells having stem cell characteristics are present in almost all tumours and that they are considerably involved in tumour growth and spread through metastases. Like normal stem cells, cancer stem cells can make unlimited copies of themselves and to a certain extent can develop into other, less malignant cell types. For this reason, it is believed that the tissue heterogeneity observed in most cancer types is caused by cancer stem cells, similar to the way that normal stem cells can produce organs with complex structures. In technical terminology we refer to the Prof. Lukas Sommer, PhD Head of the Division of Cell and Developmental Biology at the Institute of Anatomy at the University of Zurich

56 hierarchical structure of a tumour, which had its origins in one cancer stem cell from which all other tumour cells derived. their growth conditions, and their potential for spreading are dependent upon the tissue of origin and thus on the type of cancer. Cancer stem cells a new perspective in research and therapy With the discovery and experimental investigation of cancer stem cells, the way of looking at how cancer could be treated must be reconsidered. Namely, traditional therapy strategies cannot or can only insufficiently reach cancer stem cells. For example, chemotherapies aim to stop the growth and survival of the cancer as a whole. But cancer stem cells appear to possess a specific protective mechanism that allows them to send toxic chemical substances out of the cell. And so, chemotherapies seem to destroy a large part of the tumour cells but without being able to get to the root of the actual cause of the carcinogenesis. Cancer recurrence following chemotherapy could therefore be due to just a few cancer stem cells surviving in the patient s body. For this reason, cancer stem cell research must find new ways to fight cancer. Here the focus is on targeted destruction of the cancer stem cells producing the tumour. But methods are also being tested that specifically block the cell division of cancer stem cells or that accelerate their differentiation into less malignant cells. To be able to implement these new types of strategies of cancer therapy, research is needed on the molecular and cellular characteristics and growth conditions of cancer stem cells in different tumour types. As for normal stem cells, it can also be assumed for cancer stem cells that their characteristics, Cancer stem cells have already been demonstrated in various types of cancer in different organs, such as breast cancer, colon cancer, brain tumours, different forms of blood cancer (leukaemias) and some other cancers. Depending on the cancer type and on the patient, cancer stem cells in the tumour tissue appear to differ in number. In our research, we are mainly studying malignant skin cancer (melanoma). This type of cancer is extremely aggressive, and the incidence rate of melanoma is rising. Melanoma develops from a malignant change in melanocytes, which are pigment cells and, in developmental biology, develop from what is called the neural crest. The neural crest is a structure in the embryo with great development potential. Not only pigment cells but also nerve cells in the peripheral nervous system, for example, and facial cartilage and bones derive from the neural crest. To be able to build these structures, neural crest stem cells must divide substantially and move across long distances in the embryo. Since pigment cells in the skin also derive from neural crest stem cells, we raised the question as to whether these normal stem cells could have something to do with the cause of skin cancer. We supposed that possible cancer stem cells in the melanoma could show the characteristics of normal neural crest stem cells. That kind of connection could also explain why melanoma cells are so aggressive why they can multiply so strongly and spread through tissue to form metastases. And in fact, in numerous melanoma biopsies we found cells that clearly showed the features of neural crest stem cells. In

cooperation with dermatologists and pathologists at University Hospital Zurich, we made the important discovery that the number of these cells in the patient s tumour was connected with the course of the disease: The higher the number of cells with characteristics of neural crest stem cells that are found in a biopsy, the greater the probability of metastasis and of the patient dying of cancer. Inhibition of melanoma stem cells Thanks to our experience in the area of neural crest development, we were able to more precisely characterize these tumour cells and test their cancer-producing effect in animal models. In these experiments, the cells prove to be actual melanoma stem cells that can multiply arbitrarily and are responsible for tumour growth in animal models. This finding is not undisputed, as no cells having stem cell characteristics could be found in melanoma in research work conducted in the United States. This also shows that research in this area is still in its beginnings. In particular, researchers need to develop standard protocols for how cancer cells are removed from the tumour and then cultivated. For example, we were able to demonstrate melanoma stem cells only using refined methods by which the tumour tissue was treated as carefully as possible. In addition, we discovered that melanoma stem cells have a special ability to evade detection by the immune system. Finally, this research work can create a foundation for the development of new strategies in cancer therapy. For example, target structures for therapies could be identified by comparing normal stem cells and cancer stem cells. Based on this, genetic characteristics and cellular properties of cancer stem cells are determined. The knowledge of stem cell-specific biomarkers and growth factors could aid the discovery of pharmaceutically active substances that inhibit cancer stem cell development. By using this approach, in cooperation with the Institute of Pharmaceutical Sciences at ETH Zurich, we have already identified chemical substances that suppress the division of melanoma stem cells and, in animal models at least, counteract with tumour formation. However, the exact mechanisms of how these substances work must still be investigated, and it will take some time and more research work before their clinical application with patients can be tested. However, it is definitely conceivable that knowledge gained via melanoma stem cells could considerably improve the therapy approaches available today. To achieve these goals, there are still many questions that must be clarified. Do tumour stem cells derive from normal stem cells? Do they form tumour tissue hierarchically, as in the healthy organ? Or is the opposite developmental direction in the tumour also possible, so that tumour cells without stem cell characteristics can again become tumour stem cells under certain conditions? That kind of neoplasm of cancer stem cells could take place in the course of metastasis or under the influence of the immune system, for example. If that were so, the aim of therapy would perhaps not consist so much in eliminating a certain (stem) cell population in the tumour. Instead, 57

58 the attempt should be made to stop the specific molecular processes of stem cell multiplication and in this way to block the fatal activity of the cancer stem cells. Extensive investigations of this kind can only be successful through cooperation among different research groups that complement each others competencies. Here, synergies between stem cell biologists, pathologists, clinicians, and pharmaceutical scientists are imperative. This is the only way we can increase our understanding of cancer stem cells and their effect and that is urgently needed if we want to be able to possibly establish new specific and efficient strategies in cancer therapy. Prof. Lukas Sommer, PhD Lukas Sommer has been full professor and head of the Division of Cell and Developmental Biology at the Institute of Anatomy at the University of Zurich since 2007. He completed undergraduate studies in biology at the Biocenter in Basel, Switzerland, and received his PhD in 1992 at the Swiss Institute for Experimental Cancer Research (ISREC) in Lausanne. After conducting research as a postdoctoral fellow at California Institute of Technology (CALTECH) in the United States, he returned to Switzerland in 1997 to join the Institute of Cell Biology at ETH Zurich, where he worked as a group leader and then as assistant professor. Phone +41 (0)44 635 54 43 lukas.sommer@anatom.uzh.ch www.anatom.uzh.ch/research/divisionsommer_en.html

Basic biomedical research List of completed research projects from July 2008 to December 2010 Ballmer-Hofer Kurt OCS 02100-08-2007 CHF 205,700. Biomolekulare Forschung, Paul Scherrer Institut (PSI), Villigen Structural and functional analysis of ligand-mediated activation of VEGF receptor 2; identification and characterization of structural motifs for the development of new receptor inhibitory drugs for anti-vascular tumor therapy Beermann Friedrich OCS 01500-02-2004 CHF 247,344. Institut suisse de recherche expérimentale sur le cancer (ISREC), Faculté sciences de la vie, EPF de Lausanne, Lausanne In vivo screening of candidate genes in melanoma 59 Bentires-Alj Mohamed OCS 01922-08-2006 CHF 275,400. Friedrich Miescher Institut für biomedizinische Forschung (FMI), Basel Role of GAB2/SHP2 and 11q13 amplification in breast cancer Brunner Thomas OCS 02025-02-2007 CHF 176,900. Institut für Pathologie, Universität Bern, Bern Characterization and role of extra-adrenal glucocorticoid synthesis in colorectal cancer Christofori Gerhard OCS 01932-08-2006 CHF 305,400. Institut für Biochemie und Genetik, Departement Biomedizin, Universität Basel, Basel Podoplanin-mediated signalling and its role in collective cell invasion and metastasis formation Citi Sandra OCS 01916-08-2006 CHF 195,000. Département de biologie moléculaire, Sciences III, Université de Genève, Genève The role of tight junction proteins in epithelial morphogenesis and differentiation Donda Alena OCS 02248-08-2008 CHF 138,300. Département de biochimie, Université de Lausanne, Epalinges CD1d-anti tumor bifunctional molecules to redirect the innate and adaptive immune responses to the tumor site Dufour Jean-François OCS 02112-08-2007 CHF 209,900. Signal Transduction Group, Institut für klinische Pharmakologie, Universität Bern, Bern Roles of mtorc2 and mtoc1 in hepatocellular carcinoma Continuation in the project: Dufour Jean-François KFS 02541-02-2010 CHF 202,200. Institut für klinische Pharmakologie, Universität Bern, Bern Hepatocarcinogenic roles of mtor, raptor and rapamycins in absence of Pten Duration: 01.08.2010 01.08.2013 Frei Christian OCS 01575-08-2004 CHF 167,000. Institut für Zellbiologie, ETH Zürich, Zürich The function of Drosophila hypoxia-inducible factor (HIF-1) and its transcriptional targets in cellular growth control Frey-von Matt Brigitte M. KLS 02015-02-2007 CHF 246,400. Departement für Nephrologie und Hypertonie, Inselspital, Bern Androgen-mediated gene delivery (AMGD) Gasser Susan OCS 02126-08-2007 CHF 187,700. Friedrich Miescher Institut für biomedizinische Forschung (FMI), Basel The RPA70 interaction domain of Sgs1 contributes to both replication checkpoint activation and fork stability Gönczy Pierre OCS 01676-02-2005 CHF 171,100. UPGON, Institut suisse de recherche expérimentale sur le cancer (ISREC), Faculté sciences de la vie, EPF de Lausanne, Lausanne Coupling cell polarity and cell division in C. elegans embryos: Novel insights into proliferation control mechanisms

Gönczy Pierre KLS 02024-02-2007 CHF 335,100. UPGON, Institut suisse de recherche expérimentale sur le cancer (ISREC), Faculté des sciences de la vie, EPF de Lausanne, Lausanne Mechanisms of centrosome duplication in C. elegans and human cells: From model organism towards therapeutic opportunities Grassi Fabio OCS 01933-08-2006 CHF 174,300. Istituto di ricerca biomedica (IRB), Bellinzona Sinergy between oncogenic Notch and pre-t cell receptor (pre-tcr) signalling microdomains in leukemogenesis Hall Michael N. KLS 01991-02-2007 CHF 350,500. Departement Biozentrum, Universität Basel, Basel Proteomic analysis of the cancer-promoting mtor pathway 60 Heim Markus Hermann OCS 02192-02-2008 CHF 245,200. Klinik für Gastroenterologie und Hepatologie, Universitätsspital Basel, Basel Hepatocarcinogenesis in chronic hepatitis C Hemmings Brian A. OCS 01667-02-2005 CHF 271,350. Friedrich Miescher Institut für biomedizinische Forschung (FMI), Basel Role of protein kinase B (PKB/Akt) in cell transformation and cancer Hemmings Brian A. OCS 01942-08-2006 CHF 275,400. Friedrich Miescher Institut für biomedizinische Forschung (FMI), Basel The role of human protein kinase NDR in cell morphogenesis, cell division, growth control and cancer Herr Winship OCS 02047-02-2007 CHF 301,900. Centre intégratif de génomique (CIG), Faculté de biologie et de médecine, Université de Lausanne, Lausanne HCF-1 regulation of genomic stability during cell division Hübscher Ulrich OCS 01996-02-2007 CHF 251,800. Institut für Veterinärbiochemie und Molekularbiologie, Universität Zürich, Zürich Repair of oxidation damages in DNA: DNA synthesis over lesions by posttranslationally modified human DNA polymerase Huelsken Joerg OCS 01838-02-2006 CHF 336,600. UPHUE, Institut suisse de recherche expérimentale sur le cancer (ISREC), Faculté des sciences de la vie, EPF de Lausanne, Lausanne Role of inflammation in Wnt-mediated tumorigenesis Hynes Nancy KLS 02187-02-2008 CHF 47,600. Friedrich Miescher Institut für biomedizinische Forschung (FMI), Basel Characterisation of the role of PN-1 in breast cancer and its potential as a therapeutic target Janscak Pavel OCS 01730-08-2005 CHF 221,500. Institut für molekulare Krebsforschung, Universität Zürich, Zürich Study of the role of the human mismatch repair system in telomere metabolism Krek Wilhelm OCS 01787-08-2005 CHF 335,500. Institut für Zellbiologie, ETH Zürich, Zürich Roles of F-box protein Skp2-based E3 ubiquitin protein ligases in cell cycle control and neoplastic signalling Continuation in the project: Krek Wilhelm KFS 02690-08-2010 CHF 226,000. Institut für Zellbiologie, ETH Zürich, Zürich Roles of the URI oncoprotein in B-RAF-signaling and melanoma cancer cell proliferation Duration: 01.02.2011 01.02.2013 Lange Norbert OCS 01948-08-2006 CHF 163,200. Laboratoire de pharmaceutique et de biopharmacie, Section des sciences pharmaceutiques, Université de Genève, Genève Synthesis and evaluation of new water soluble polymeric photosensitizer prodrugs for photodynamic therapy MacDonald Hugh Robson OCS 01863-02-2006 CHF 346,300. Centre Ludwig de recherche sur le cancer, Epalinges The role of proto-oncogenes in hematopoietic and cancer stem cells

Moradpour Darius OCS 01762-08-2005 CHF 250,700. Division de gastro-entérologie et d hépatologie, Centre hospitalier universitaire vaudois (CHUV), Lausanne Development of a model system to study coinfection by hepatitis B and C viruses the major causes of hepatocellular carcinoma Müller Anne OCS 02099-08-2007 CHF 191,500. Institut für molekulare Krebsforschung, Universität Zürich, Zürich The molecular pathogenesis of Helicobacter pylori-induced mucosa-associated lymphoid tissue (MALT) lymphoma in an animal model: Analysis of the role of tumor infiltrating accessory cells in vivo and ex vivo and of the specificity of tumor immunoglobulin Continuation in the project: Müller Anne KFS 02640-08-2010 CHF 293,700. Institut für molekulare Krebsforschung, Universität Zürich, Zürich The molecular pathogenesis of Helicobacter pylori-induced mucosa-associated lymphoid tissue (MALT) lymphoma: Analysis of the role of small regulatory RNAs in lymphomagenesis and high grade transformation Duration: 01.11.2010 01.11.2013 61 Nägeli Hanspeter KLS 01827-02-2006 CHF 117,700. Institut für Veterinärpharmakologie und -toxikologie, Universität Zürich, Zürich Regulation of nucleotide excision repair activity by protein modifiers Ochsenbein Adrian F. OCS 01627-02-2005 CHF 274,300. Universitätsklinik für medizinische Onkologie, Inselspital, Bern Immunosurveillance of chronic myeloid leukemia in mice Orend Gertraud OCS 01875-02-2006 CHF 304,100. Unité Inserm 682, Institut national de la santé et de la recherche médicale (INSERM), Strasbourg, France Analysis of a potential oncogenic function of tenascin-c and tenascin-w in colon cancer Pabst Thomas OCS 01833-02-2006 CHF 249,000. Universitätsklinik für medizinische Onkologie, Inselspital, Bern The myeloid key transcription factor CEBPA and the pathophysiology of acute myeloid leukemia Pelkmans Lucas OCS 02111-08-2007 CHF 198,000. Institut für molekulare Systembiologie, ETH Zürich, Zürich How focal adhesion kinase (FAK) controls membrane partitioning and endocytosis of cell adhesion components in normal and in cancer cells Peter Matthias OCS 02189-02-2008 CHF 229,400. Institut für Biochemie, ETH Zürich, Zürich Regulation of genome stability by Rtt101p/cullin4-based E3-ubiquitin ligases in yeast and mammalian cells Plückthun Andreas OCS 02128-08-2007 CHF 215,400. Biochemisches Institut, Universität Zürich, Zürich Tumor targeting of ErbB2 with designed ankyrin repeat proteins Pruschy Martin OCS 02129-08-2007 CHF 223,100. Labor für molekulare Radiobiologie, Klinik für Radio-Onkologie, UniversitätsSpital Zürich, Zürich Microtubule interference as target for combined cancer therapy with ionizing radiation Radtke Freddy OCS 01560-08-2004 CHF 140,600. UPRAD, Institut suisse de recherche expérimentale sur le cancer (ISREC), Faculté des sciences de la vie, EPF de Lausanne, Lausanne The role of Notch2 in murine epidermis Radtke Freddy KLS 01840-02-2006 CHF 346,300. UPRAD, Institut suisse de recherche expérimentale sur le cancer (ISREC), Faculté des sciences de la vie, EPF de Lausanne, Lausanne The role of Notch1 signalling in acute lymphoblastic T-cell leukaemia (T-ALL) Renner Christoph OCS 02119-08-2007 CHF 192,200. Klinik und Poliklinik für Onkologie, Medizinbereich Innere Medizin Onkologie, UniversitätsSpital Zürich, Zürich Selective inhibition of intratumoral regulatoy T-cells by antibody-gitr ligand fusion proteins

Romero Pedro OCS 02011-02-2007 CHF 173,600. Division d oncologie clinique, Centre Ludwig de recherche sur le cancer, Lausanne Impact of lentiviral cancer vaccines on the anti-tumor T-cell response in vivo Rüegg Curzio OCS 02020-02-2007 CHF 275,600. Division de pathologie expérimentale, Université de Fribourg, Fribourg Role of integrins and Cyr61/CCN1 in tumor metastasis: Unraveling mechnisms and development of novel integrin inhibitors Rufer Nathalie OCS 01995-02-2007 CHF 204,500. Centre Ludwig de recherche sur le cancer, Université de Lausanne, Lausanne Defining molecular, structural and functional T-cell receptor properties of melanoma-specific human CD8 + T lymphocytes 62 Ruiz i Altaba Ariel OCS 01857-02-2006 CHF 321,900. Département de génétique médicale et de développement, Faculté de médecine, Université de Genève, Genève Determination of the extent of participation of the sonic hedgehog-gli signalling pathway in human gliomas and in their cancer stem cells Schär Primo OCS 02193-02-2008 CHF 283,400. Institut für Biochemie und Genetik, Departement Biomedizin, Universität Basel, Basel The role of thymine DNA glycosylase in the maintenance of genetic and epigenetic stability and the suppression of tumorigenesis Continuation of the project: Schär Primo OCS 01868-02-2006 CHF 210,800. Institut für Biochemie und Genetik, Departement Biomedizin, Universität Basel, Basel Clarification of newly emerging roles of DNA repair in mediating the cytotoxicity of 5-fluorouracil and in the maintenance of epigenetic stability Schübeler Dirk KLS 01865-02-2006 CHF 179,500. Friedrich Miescher Institut für biomedizinische Forschung (FMI), Basel Role and plasticity of DNA methylation in stem cell pluripotency and cancer Schwaller Jürg OCS 01830-02-2006 CHF 228,100. Forschungsgruppe Kinderleukämie, Departement Biomedizin, Universitätsspital Basel, Basel PIM serine/threonine kinases as potential therapeutic targets in human hematological malignancies Skoda Radek C. OCS 01742-08-2005 CHF 339,000. Forschungsgruppe experimentelle Hämatologie, Departement Biomedizin, Universitätsspital Basel, Basel Pathogenesis of myeloproliferative disorders Stamenkovic Ivan OCS 01656-02-2005 CHF 173,900. Institut universitaire de pathologie de Lausanne (IUP), Centre hospitalier universitaire vaudois (CHUV), Lausanne Analysis of the molecular mechanisms underlying the pathogenesis of EWING S family tumors Suter Beat OCS 01834-02-2006 CHF 243,000. Institut für Zellbiologie, Universität Bern, Bern Control of the cell cycle function of Xpd and Cdk7 Tschan Mario P. OCS 01823-02-2006 CHF 203,800. Medizinische Onkologie/Hämatologie, Departement für klinische Forschung, Universität Bern, Bern Regulation of the DMP1-ARF-p53 tumor suppressor pathway in normal and leukemic hematopoiesis Walker Paul R. OCS 01754-08-2005 CHF 269,200. Centre d oncologie, Hôpitaux universitaires de Genève (HUG), Genève Exploration of intracerebral immune responses in a spontaneous astrocytoma model and their exploitation in novel cancer therapies Wymann Matthias OCS 01924-08-2006 CHF 293,500. Forschungsgruppe Krebs und Immunbiologie, Departement Biomedizin, Universität Basel, Basel Phosphoinositide 3-kinases in melanoma

Zaugg Kathrin OCS 02009-02-2007 CHF 195,500. Labor für angewandte Radio-Onkologie, UniversitätsSpital Zürich, Zürich Elucidating the role of the hypoxia-protective gene CPT1C in carcinogenesis Continuation in the project: Zaugg Kathrin KLS 02569-02-2010 CHF 78,000. Labor für angewandte Radio-Onkologie, UniversitätsSpital Zürich, Zürich Elucidating the role of the hypoxia-protective gene CPT1C (Carnitine Palmitoyl-transferase 1C) in carcinogenesis Duration: 01.05.2010 01.05.2011 63 Basic biomedical research Presentation of completed research projects from July 2008 to December 2010 Ballmer-Hofer Kurt Structural and functional analysis of ligand-mediated activation of VEGF receptor 2; identification and characterization of structural motifs for the development of new receptor inhibitory drugs for anti-vascular tumor therapy (OCS 02100-08-2007) Vascular Endothelial Growth Factors (VEGFs) constitute a family of proteins that regulate blood and lymphatic vessel development. Vessel formation and the maintenance of proper vessel organization are absolutely required for sustaining organ function in higher organisms. Aberrant vessel formation is associated with various diseases, such as arteriosclerosis, retinopathies, lymphoproliferative or rheumatoid disease, and in tumour growth where newly formed vessels allow cancer cells to grow more rapidly and to disseminate into the entire body. Tumour vascularization is a hallmark of many types of highly aggressive malignancies, such as breast, colon and stomach cancer. VEGFs bind to receptors expressed on the surface of cells and thereby activate their target cells to migrate, proliferate and ultimately to form new vessels. VEGF binding to cell surface exposed receptors induces changes in receptor structure that lead to receptor activation thereby giving rise to the generation of signals transmitted across the cell membrane to the intracellular milieu of the cell. We investigated the molecular mechanism of VEGF receptor activation with the aim to develop new receptor inhibitors applicable for the treatment of disease associated with aberrant vessel formation. Studying the structure of VEGF receptors and VEGF-receptor complexes, we found that VEGF binding drastically alters the three-dimensional structure of the receptor. These structural changes are re sponsible for receptor activation and give rise to signals that promote the formation of new vessels. We investigated VEGF receptors using electron microscopy, X-ray crystallography and small angle solution scattering techniques. The structural and functional information gained in this project was used to develop a comprehensive molecular model of receptor function that was essential for further progress in the development of new receptor antagonists for future medical applications. Based on the newly gained insights into the activation mechanism of VEGF receptors, we developed new antibody-like molecules to block receptor activation. In a follow up study we are now investigating the potential of these new molecular tools to block tumour growth in an animal model. Prof. Dr. Kurt Ballmer-Hofer Laboratory of Biomolecular Research Molecular Cell Biology Paul Scherrer Institut Bldg. OFLC 102 CH-5232 Villigen-PSI Phone +41 (0)56 310 41 65 Fax +41 (0)56 310 52 88 kurt.ballmer@psi.ch

64 Beermann Friedrich In vivo screening of candidate genes in melanoma (OCS 01500-02-2004) Melanoma is a malignant tumour arising from melanocytes, which are pigment cells derived from the neural crest. In the mouse, melanoma does not occur spontaneously, and, thus transgenic mouse models are used to address genetic changes leading to melanomagenesis or to study melanocyte development. In this project we wanted to address the role of candidate genes, first in melanocyte biology and homeostasis and later in melanoma development. We used transgenic mouse models to analyze the Notch signalling pathway in normal melanocyte biology, and to address the lack of the oncogene c-myc during melanocyte development. Moreover, we addressed the relevance of b-catenin directly in a mouse model of melanoma. Notch signalling: Notch has been shown to be expressed in mouse melanocytes and human melanoma. Using transgenic mouse models, we showed that deletion of Notch signalling in the melanocyte lineage induces precocious hair greying, the intensity of which depends on the number of deleted alleles of Notch1 and Notch2. Further histological analysis showed that this is due to a loss of melanocyte precursors as well as melanocyte stem cells after birth. This confirms that Notch signalling affects hair pigmentation and melanoblast population in a gene dosage-dependent manner. When we overexpressed Notch in melanocytes, we could not prevent normal hair greying or induce melanoma tumours, indicating that Notch signalling by itself is not sufficient for melanoma formation. The c-myc oncogene: c-myc is expressed in many tumours, including melanoma. To understand its role in melanocytes, we removed it specifically in a transgenic mouse model. Removal of c-myc leads to a hair greying phenotype that is not due to an effect in stem cells. In contrast to Notch, the phenotype is caused by a problem in proliferation during midgestation. These results indicated that c-myc is an important player in melanocyte biology, and we plan to address its role in a mouse model of melanoma. b-catenin: This protein is part of the Wnt signalling pathway and has been reported to be mislocalized in human melanoma. In collaboration with Lionel Larue s group (Orsay, France), we used mice that express a stable form of b-catenin that leads to repression of the tumour suppressor p16 by binding to its promoter. Double transgenic animals expressing both an activated N-Ras oncogene and an activated b-catenin had a high incidence of melanoma with a short latency period. Histopathological analysis suggested that most melanomas arose from melanocytes located in the hair follicles. The results thus reveal that synergy between the Wnt and mitogen-activated protein (MAP) kinase pathways (due to activated N-Ras) may represent an important mechanism underpinning the genesis of melanoma. Dr Friedrich Beermann Institut suisse de recherche expérimentale sur le cancer (ISREC) Faculté Sciences de la vie EPF de Lausanne (EPFL) Station 19, Bâtiment SV CH-1015 Lausanne Phone +41 (0)21 693 07 27 friedrich.beermann@epfl.ch Bentires-Alj Mohamed Role of GAB2/SHP2 and 11q13 amplification in breast cancer (OCS 01922-08-2006) Each year 1.1 million new cases of breast cancer will occur among women worldwide, and 400,000 women will die of this disease. Although progress has been made in understanding breast tumour biology, most of the relevant molecules and pathways remain undefined. Their delineation is critical to a rational approach to breast cancer therapy. This project focuses on the roles of the signalling proteins GAB2/SHP2 (part 1) and on amplification of the chromosomal region 11q13 (part 2) in breast cancer. To address these questions, we used a combination of 3D cultures and xenograft models. In the first part, we found that inhibition of SHP2 dramatically reduces proliferation and reverses the invasiveness of transformed breast cells grown in 3D cultures. Moreover, SHP2 knockdown after tumour formation blocks tumour progression. In the second part, we found two highly defined genomic regions of 11q13 amplification in breast tumours and identified 8 genes that are co-amplified and co-overexpressed in these tumours. Taken together, our studies revealed potential therapeutic targets for the treatment of breast cancer. Dr. Mohamed Bentires-Alj Friedrich Miescher Institut für biomedizinische Forschung (FMI) Maulbeerstrasse 66 CH-4058 Basel Phone +41 (0)61 697 40 48 Fax +41 (0)61 697 39 76 bentires@fmi.ch Brunner Thomas Characterization and role of extra-adrenal glucocorticoid synthesis in colorectal cancer (OCS 02025-02-2007) Glucocorticoids are important immunoregulatory steroids, produced mainly in the adrenal glands. However, our past research demonstrated that the epithelial cells of the intestinal crypts are capable of producing glucocorticoids in response to immune cell activation and that intestinal glucocorticoids contribute to the control of local immune responses. The aim of this study was to investigate whether colon carcinoma can produce glucocorticoids, how tumour glucocorticoid synthesis is regulated and whether tumour-derived glucocorticoids actively suppress immune cells. The expression and induction of transcription factors and enzymes involved in the synthesis of cortisol from cholesterol in colon carcinoma cell lines as well as primary tumours was investigated using quantitative PCR and luciferase reporter assays. The role of the transcription factor LRH-1 (liver receptor homolog-1) in the regulation of tumour glucocorticoid synthesis was assessed using overexpression and RNA interference. Cortisol production was measured using radioimmunoassay, thin layer chromatog

raphy and bioassay. The suppressive and apoptosis-inducing activity of tumour glucocorticoids was assessed on activated T cells and thymocytes. Our study could show that colon carcinoma cell lines as well as primary tumours express all enzymes required for synthesis of glucocorticoids and secrete bioactive cortisol. Similar to primary intestinal epithelial cells, LRH-1 was found to play a critical role in the regulation of tumour glucocorticoid synthesis and to be overexpressed in many primary colon carcinomas. Cortisol produced by colon carcinomas potently suppressed T cell activation and induced apoptosis in glucocorticoid-sensitive thymocytes. This is the first demonstration of glucocorticoid synthesis in tumours not derived from steroidogenic organs, and it suggests that tumour-derived glucocorticoids could play an important role in the regulation of anti-tumour immune responses. Whereas the glucocorticoid synthesis in primary epithelial cells contributes to intestinal immune homeostasis and prevents intestinal inflammation, glucocorticoid synthesis in colon carcinoma cells may represent a tumour-promoting factor. Prof. Dr. Thomas Brunner Lehrstuhl für biochemische Pharmakologie Fachbereich Biologie Universität Konstanz D-78457 Konstanz Deutschland Phone +49 (0)7531 88 53 70 thomas.brunner@uni-konstanz.de

66 Christofori Gerhard Podoplanin-mediated signalling and its role in collective cell invasion and metastasis formation (OCS 01932-08-2006) Tumour invasion is the first step in the formation of metastases, which is the actual cause of death in most cancer fatalities. Originally, tumour cell invasion was thought to be dependent on the loss of cell-cell adhesion and on single cell migration. However, we showed previously that cancer cells can also invade the surrounding tissue in a cell collective. We identified the small mucin-like transmembrane protein podoplanin as a key regulator of collective cell migration and invasion, and we investigated the functional role of podoplanin during tumour progression. For example, expression of podoplanin in tumour cells of a transgenic mouse model of pancreatic cancer caused tumour cell invasion in the absence of any loss of cell-cell adhesion. Moreover, forced expression of podoplanin in breast cancer cell lines also leads to increased cell migration and invasion without loss of cell-cell adhesion. Finally, podoplanin expression correlates with tumour invasion in squamous cell carcinomas (SCC) of various organs. Together, the results indicate that podoplanin employs a novel molecular pathway of inducing collective tumour cell invasion. However, the regulation of podoplanin expression in the invading cancer front as well as the molecular mechanisms by which podoplanin confers its pro-migratory and pro-invasive function have remained elusive. In the past years, we investigated how the curious expression of podoplanin in the invasive cancer front is regulated and how podoplanin mediates collective cancer cell migration. We isolated the podoplanin-expressing invading cells of squamous cell carcinoma by laser capture microscopy of tissue sections and employed gene expression profiling to determine the differences between podoplanin-expressing and podoplanin-negative cancer cells. The podoplanin-expressing cells exhibited a significant upregulation of inflammatory signalling pathways, including the interferon-g, tumour necrosis-factor-a (TNF-a) and transforming growth factor-b (TGF-b) pathways. Subsequent studies showed that indeed podoplanin expression is induced by the treatment of cancer cells with these inflammatory cytokines. We are currently ablating these signalling pathways in squamous cell carcinoma cells in culture and in mouse models to study the effect of the lack of these inflammatory signalling pathways on podoplanin expression and collective cell invasion. The pro-migratory function of podoplanin is at least in part mediated by the remodelling of the actin cytoskeleton of cancer cells. We have set out to identify binding partners of podoplanin, which potentially play critical roles in transmitting the pro-migratory signals of podoplanin. However, various biochemical analyses did not identify proteins that interact with podoplanin in a specific and robust manner. From these experiments we conclude that podoplanin exerts its pro-migratory and invasive function via pathways that do not include a direct interaction with other signalling proteins. Based on this and other evidence, we are currently testing the possibility that podoplanin exerts its signalling functions by clustering on the cell surface and employing its highly glycosylated ex tracellular domain to act as a low affinity receptor for chemokines and growth factors. The elucidation of podoplanin s mode of action in inducing collective cell invasion provides important new insights into the molecular mechanisms of cancer cell invasion and metastasis formation. Prof. Dr. Gerhard Christofori Institut für Biochemie und Genetik Departement Biomedizin Universität Basel Mattenstrasse 28 CH-4058 Basel Phone +41 (0)61 267 35 62 Fax +41 (0)61 267 35 66 gerhard.christofori@unibas.ch Citi Sandra The role of tight junction proteins in epithelial morphogenesis and differentiation (OCS 01916-08-2006) The majority of cancers originate from epithelial cells and tissues, which cover all surfaces and cavities of the body (skin, gastrointestinal, respiratory and urinary tracts, etc.) and constitute glands (breast, kidney, liver, pancreas). Normal epithelial cells proliferate in a controlled fashion, are closely bound together and have a characteristic polarized shape, with apical, basal and lateral sides. When epithelial cells become cancerous, they dedifferentiate and lose some or most of these properties. For example, they may lose their ability to adhere to one another, lose polarity, become more motile, migrate elsewhere in the body and start to divide in an uncontrolled way, thus forming metastases. Our research focuses on the role of proteins, which constitute specialized cell-cell junctions. Junctions are structures that control adhesion between cells and are also implicated in signalling mechanisms that regulate epithelial cell growth and proliferation. There are different types of junctions, and we are focusing our attention on tight and adherens junctions, which are localized at the apicolateral border of epithelial cells. Tight junctions are involved in the maintenance of the polarized shape and also serve to form a barrier that controls the passage of molecules and pathogens across sheets of epithelial cells. Adherens junctions play a major role in cellcell adhesion and signalling mechanisms that regulate morphogenesis and cell sorting. The goal of our project was to understand the role of specific proteins of tight junctions (cingulin and paracingulin) in the establishment and maintenance of the differentiated state and signalling properties of epithelial cells, using as the main experimental approaches studies on cells in culture and on human epithelial lung cancer tissues. We made important discoveries about the role of cingulin and paracingulin in controlling the activities of RhoA and Rac1, molecular switches that regulate the assembly of the cytoskeleton and also in controlling proliferation and gene expression in epithelial cells. The activities of RhoA

and Rac1 are frequently altered in cancer tissues, which could account for their altered migratory properties. Therefore, our studies are directly relevant to understanding the molecular mechanisms of regulation of signalling pathways that are altered in cancer. We further studied the dynamics of cingulin and paracingulin in living cells and clarified differences in their behaviour and localization, which will help to clarify their redundant and non-redundant functions. Using antibodies that we developed in our laboratory, we studied the expression of cingulin in different types of human lung tumours in collaboration with the Department of Clinical Pathology at Geneva University Medical School. These results, and results obtained using several other antibodies against tight junction proteins and reverse-transcription polymerase chain reaction to assess gene expression, allowed us to propose a new molecular classification of lung carcinomas based on expression of specific tight junction proteins. Recently, we identified a novel adherens junction protein, PLEKHA7, against which we developed specific monoclonal antibodies, and which we would like to use to examine its expression in human cancer, which has not been done so far. In summary, the results that we obtained have provided new information on the function of certain tight junction proteins, their role in the process of differentiation and cancer formation and their possible use in cancer diagnosis. In addition, our studies led to the discovery and preliminary characterization of a new adherens junction protein. Dr Sandra Citi Département de biologie moléculaire Sciences III Université de Genève 4, boulevard d Ivoy CH-1205 Genève Phone +41 (0)22 379 61 82 Fax +41 (0)22 379 68 68 sandra.citi@unige.ch Donda Alena CD1d-antitumor bifunctional molecules to redirect the innate and adaptive immune responses to the tumor site (OCS 02248-08-2008) When activated by the CD1d protein expressed by antigen-presenting cells (APC), invariant natural killer T (inkt) cells are able to transactivate the innate and adaptive immune system, and their antitumour activity is well demonstrated. In the initial phase of this project, we showed that repeated injections of a soluble recombinant CD1d protein loaded with the glycolipid ligand a-galactosyl ceramide (agalcer) was able to induce sustained inkt cell activation, in contrast to the short-lived stimulation obtained with the ligand alone. Importantly, when CD1d was fused to an antitumour antibody fragment (CD1danti-HER2), delayed tumour growth was obtained, associated with tumour infiltration by inkt, NK and T lymphocytes, all able to kill cancer cells. In order to get closer to a clinical application, the second phase of this project included the following aspects: 1) We extended the targeting of CD1d to different types of cancer. In addition to the targeting of HER2 over-ex pressed in breast cancer, we developed a CD1d-anti-CEA fusion protein specific of a tumour antigen over-expressed in colon cancer, as well as a CD1d-anti-VEGFR3 fusion protein targeting a marker of tumour neo-vascularization. Sustained inkt activation and inhibition of tumour growth by these three CD1d bi-functional proteins were evidenced in several tumour models. 2) At the cellular level, in vivo and in vitro experiments demonstrated that inkt cell activation by soluble CD1d proteins prevented the negative retro-control of PD-1/PD-L1 interaction that normally occurs during cell-cell interaction between inkt and APCs, leading to their subsequent unresponsiveness. The attenuated PD-1 upregulation largely explains the sustained inkt cells obtained with recombinant CD1d proteins, which is optimal for a systemic treatment. 3) Several in vivo experiments have shown that the adjuvant effect of CD1d-mediated therapy on the adaptive immune response remains limited by immunosuppressive mechanisms developed in the periphery and at the tumour site. In particular, the expansion of myeloid-derived suppressor cells (MDSCs) induced by the tumour environment is known to inhibit the antitumour immune response and remains a challenge for cancer immunotherapy. MD SCs act by various mechanisms, among which are several enzymatic activities such as arginase 1, which depletes arginine essential for the activity of T lymphocytes. We could demonstrate the inhibitory effect of arginase 1 on CD1d-mediated therapy in a mouse model in which arginase 1 has been eliminated in the myeloid compartment. In these mice, the antitumour effect of CD1d-antitumour treatment was indeed far more potent than in mice with active arginase 1. In view of these results, we are testing chemotherapeutic agents able to deplete preferentially MDSCs, such as 5-fluorouracil. The next step is to combine CD1d-mediated immunotherapy with chemotherapy, and these protocols will be tested in two transgenic mouse models developing spontaneous tumours, representative of melanoma tumours and prostate cancer in humans. Combination of multiple anti-cancer therapies is more and more considered, as it can result in a synergistic tumour inhibition and limit tumour escape. Dr Alena Donda Département de biochimie Université de Lausanne Chemin des Boveresses 155 CH-1066 Epalinges Phone +41 (0)21 692 58 57 alena.donda@unil.ch 67

68 Frei Christian The function of Drosophila hypoxiainducible factor (HIF-1) and its transcriptional targets in cellular growth control (OCS 01575-08-2004) Several studies in recent years have shown that tumours differ significantly from normal tissues: Primary tumour and cancer cells are often exposed to a low oxygen environment, called hypoxia, and have to adapt their metabolism accordingly. Essential for the adaptation is the transcription factor HIF (hypoxia-inducible factor), which induces genes that are required for survival and growth of cancer cells under such conditions. Whereas HIF is stabilized under hypoxia, this factor is hydroxylated and degraded under a normal/high oxygen environment. The enzymes that hydroxylate HIF are PHD1, PHD2 and PHD3 (prolyl hydroxylase domain) and belong to the family of oxygen- and 2-oxoglutarate-dependent dioxygenases. Whether and how PHDs control growth and metabolism in an HIF-independent manner was not known and was the question of this study. The molecular functions of PHDs and HIF are conserved between the fruit fly Drosophila melanogaster and humans, suggesting that the cellular adaptation to hypoxia developed early during evolution. In our study, we used biochemical methods to find new PHD-interacting proteins, and we focused on proteins that would bind to PHDs in fly as well as human cells. One such protein was pyruvate kinase (PK), a glycolytic enzyme required for the synthesis of pyruvate. The human cancer cell line HeLa was used for subsequent characterization. We found that cells containing a reduced amount of PHD3 (using the RNAi methodology) show an increase in PK enzymatic activity, leading to more pyruvate. This effect was seen particularly under hypoxic conditions, suggesting that the binding of PHD3 and PK might be important for the cellular adaptation to low oxygen. Of note, PK is not a novel PHD3 hydroxylation target but is controlled by direct binding by PHD3 that blocks formation of the active tetramer form of PK. Most tumours show a characteristic increase in glucose, resulting in higher glycolytic rates. Since PK activity is reduced in response to PHD3 binding, we studied whether the cellular metabolism would adapt to low PHD3 levels. Indeed, we observed higher activity of the mitochondrial TCA cycle, an increase in reactive oxygen species and a reduction in cell proliferation. We concluded that the interaction between PHD3 and PK constitutes a novel mechanism to control glycolysis. Since PHD3 itself is a HIF target and accumulates under hypoxic conditions, this mechanism applies particularly to cells under a low oxygen environment. In the future, we would like to test whether the PHD3/PK interaction can be pharmacologically blocked, and whether this affects the growth of tumours. Project coodinator Prof. Dr. Christian Frei Institut für Zellbiologie ETH Hönggerberg HPM F38.2 Schafmattstrasse 18 CH-8093 Zürich Phone +41 (0)44 633 33 94 Fax +41 (0)44 633 13 57 christian.frei@cell.biol.ethz.ch Frey-von Matt Brigitte M. Androgen-mediated gene delivery (AMGD) (KLS 02015-02-2007) We recently developed a new procedure of transferring genes by targeting nuclear steroid receptors to achieve receptor-dependent enhanced transgene DNA expression (Rebuffat et al., Nature Biotechnology, 2001;12:1155-1161). This strategy, termed Steroid Mediated Gene Delivery (SMGD), facilitates the nuclear uptake of transfected DNA using glucocorticoid receptors (GR), which are natural cytoplasm-nucleus shuttles. We synthesized constructs consisting of the synthetic steroid dexamethasone coupled to a DNA-binding moiety. These ligand- DNA constructs translocated and expressed transgene DNA only in cells possessing the GR, an effect even more pronounced in growth-arrested cells. These results were the first proof-of-principle that a chemically modified steroid ligand can be used for cell-specific DNA delivery in vitro. A patent covers this strategy. As a potentially clinically relevant extension we proposed to apply this strategy for targeting androgen receptors (AR) in prostate cancer cells. These cells frequently become androgen-independent and therapy-resistant partially attributed to alterations in the AR ligand binding domain. To target prostate cancer cells with mutated ARs, we synthesized >90 steroid derivatives and a novel gene/ drug delivery vehicle. The vehicle comprises branches, each of which can be selectively and efficiently functionalized with, first, an agent that allows to cross the cell membrane and, second, an agent that facilitates the crossing of the nuclear membrane. Another branch will be used to attach a cytotoxic gene or an anticancer drug. To some extent, as a co-product this derivative library of more than 90 compounds offers an additional potential a) for androgen-mediated imaging (AMI) using positron emission tomography (PET); b) to provide clinically relevant agonists or antagonists for AR; and c) for androgenmediated gene delivery (AMGD). All three aspects are in progress. Potential 1): Out of the >90 derivatives 3 compounds have excellent binding capacities to the AR a prerequisite to be used for AMGD, AMI or as AR regulators. Since these 3 derivatives are iodinated and fluorinated, and since there is a high demand for specific PET-imaging agents, these compounds will be evaluated for PET imaging in collaboration with the Department of Nuclear Medicine at Bern University Hospital (Prof. Krause). In addition, these derivatives will be used for the AMGD strategy. Potential 2): Very recently a promising antagonist, RB346, was identified within the derivatives. Importantly, the binding affinity of this ligand to wild type and mutant ARs is the same or even better than that of bicalutamide, a drug used for prostate cancer treatment in patients. Notably RB346 maintains its antagonistic effect towards the mutant W741L without the agonist action of bicalutamide. We will now study the mechanism of action in vitro and in vivo in more detail and analyze the binding affinity of all the other ligands to selected nuclear receptors.

Potential 3): During the past two years we have designed, developed and partially synthesized an innovative novel transport vector concept. To test the functionality of this vector we used fluorescent mimics for each of the single binding elements. We present evidence of a specific docking to the prostate cancer cell, internalization and binding to AR-positive but not AR-negative cells. At present we are attempting to attach a toxin/drug/plasmid and perform in vitro studies. If successful, we will investigate this tool in control and tumour-bearing mice and analyze as recently published the efficacy by determining the apoptosis rate. Prof. Dr. Brigitte M. Frey-von Matt Departement Nephrologie und Hypertonie Inselspital Freiburgstrasse 15 CH-3010 Bern Phone +41 (0)31 632 94 39 Fax +41 (0)31 632 44 36 brigitte.frey@dkf.unibe.ch Gasser Susan The RPA70 interaction domain of Sgs1 contributes to both replication checkpoint activation and fork stability (OCS 02126-08-2007) During DNA replication, eukaryotic cells are particularly sensitive to intrinsic sources, such as fork collapse, and to extrinsic DNA damaging agents. Oncogenically transformed cells show signs of replication stress even in the absence of exogenous damaging agents. To ensure genome integrity, stalled replication forks are stabilized by the checkpoint kinases (ATR) and a RecQ helicase, which in yeast is called Sgs1 and in humans BLM (Cobb et al. 2005). BLM carries the mutations responsible for Bloom s syndrome, a cancer-prone genetic predisposition. In yeast, the ATR homologue, Mec1 and Sgs1 contribute to DNA polymerase stability independently, yet both interact with the single-strand binding heterotrimeric replication protein A (RPA). RPA was shown to recruit Mec1-Ddc2 to a stalled or damaged replication fork but also to be a target of Mec1 phosphorylation after checkpoint activation. Previous work from our laboratory also showed that RPA interacts tightly with Sgs1. To analyze if the Mec1 and Sgs1 polymerase stabilizing pathways converge on RPA, we examined the role of the Sgs1-RPA interaction in stabilizing stalled replication forks by disrupting their interaction. We mapped the Sgs1-RPA interaction site to the acidic region N-terminal of the Sgs1 helicase domain. This region contains 3 T/SQ sites which are Mec1 target sites. We created two sgs1 mutants: sgs1-r1, which lacks the RPA interaction site, and sgs1-4a, in which the phosphorylation sites are modified. These were examined for their effects on both checkpoint response and polymerase stability at stalled forks. The deletion construct reduces the affinity of Sgs1 and RPA in vivo and in vitro. We found that both this interaction site and the helicase activity of Sgs1 are important for stabilizing DNA pol a/primase at stalled forks. Unlike the synergism observed between sgs1d and the S-phase specific Mec1 mutation, mec1-100, sgs1-r1 and mec1-100 mutations are epistatic. This places sgs1-r1 downstream of mec1-100. Indeed, once the Sgs1 r1 domain is phosphorylated by Mec1, this site then binds the downstream checkpoint kinase Rad53, helping stimulate the checkpoint response to replicative stress. Our study thus links the ATR homologue and the BLM helicase in orchestration of the checkpoint response at stressed replication forks. In this way both proteins contribute to cancer prevention. They may also be useful targets for enhancing cancer cell death through combined chemotherapy. Prof. Dr. Susan M. Gasser Friedrich Miescher Institut für biomedizinische Forschung (FMI) Maulbeerstrasse 66 CH-4058 Basel Phone +41 (0)61 697 72 55 Fax +41 (0)61 697 39 76 susan.gasser@fmi.ch Gönczy Pierre Coupling cell polarity and cell division in C. elegans embryos: Novel insights into proliferation control mechanisms (OCS 01676-02-2005) Background Defective epithelial cell polarity is thought to contribute to tumour development. The PAR proteins were originally identified in the nematode C. elegans; they play a crucial role in establishing cell polarity across metazoan evolution, including in mammals. In fact, the human homologue of PAR-4 is LKB1, a tumour-suppressor protein affected in the autosomal inherited Peutz-Jeghers syndrome, exemplifying the link between cell polarity and tumour development. Despite these and other findings, the mechanisms by which cell polarity impinges on cell cycle progression are poorly understood. Specific aim We set out to analyze the mechanisms coupling PAR-dependent polarity and cell division timing using the early C. elegans embryo as a model system. Principal results We had shown previously that activation of the DNA replication checkpoint contributes to coupling polarity cues and cell cycle progression in two-cell stage C. elegans embryos, by retarding preferentially entry into mitosis in the cell located on the posterior side of the embryo. In the present study, we discovered that such coupling relies in addition on a mechanism that promotes mitosis preferentially in the anterior cell. We found that the Polo-like kinase PLK-1, an inducer of mitotic entry across eukaryotic evolution, is distributed in an asymmetric manner in twocell stage C. elegans embryos, with more protein present in the anterior. Moreover, we demonstrated that PLK-1 asymmetry is regulated by PAR-dependent polarity. We then conducted experiments that support the view that PLK-1 asymmetry is important for asynchronous division of two-cell stage C. elegans embryos. Together with the preferential retardation of mitotic entry in the posterior 69

70 cell, this novel mechanism serves to couple polarity cues with cell cycle progression during early development of C. elegans embryos. As the PAR proteins and PLK kinases are conserved across metazoan evolution, we anticipate the novel coupling uncovered here to be similarly conserved. Moreover, given that the Polo-like kinase PLK1 has been causally implicated in tumourigenesis, we expect our findings to ultimately result in advances for the understanding and treatment of cancer. Prof. Dr Pierre Gönczy Institut suisse de recherche expérimentale sur le cancer (ISREC) Faculté des sciences de la vie EPF de Lausanne (EPFL) SV 1526 Station 19 CH-1015 Lausanne Phone +41 (0)21 693 07 11 pierre.gonczy@epfl.ch Gönczy Pierre Mechanisms of centrosome duplication in C. elegans and human cells: From model organism towards therapeutic opportunities (KLS 02024-02-2007) Background The centrosome is the major microtubule-organizing centre of animal cells. There is a single centrosome early in the cell cycle, which duplicates during S phase to direct bipolar spindle assembly during mitosis, thus ensuring faithful segregation of the genetic material. Formation of a new centriole next to each existing one is critical for centrosome duplication. Failure of centrosome duplication can result in monopolar spindle assembly, excess centrosome duplication in multipolar spindle assembly and thus genome instability. Furthermore, cancer cells often exhibit aberrations in centrosome number, the severity of which correlates with tumour progression. Therefore, centrosome duplication offers unique therapeutic and diagnostic opportunities in the fight against cancer. Specific aim We set out to combine the strengths of two experimental systems, embryos of the nematode C. elegans and human cells in culture, to gain novel insights into the mechanisms of centrosome duplication. Principal results We obtained the most significant results with the C. elegans protein SAS-6 and the human protein CPAP. In C. elegans, the proteins SPD-2, ZYG-1, SAS-6, SAS-5 and SAS-4 are essential for centriole formation, but the mechanisms underlying their requirement remained unclear. During this project, we uncovered that the kinase ZYG-1 phosphorylates the protein SAS-6 at the serine residue 123 in vitro. Importantly, we showed that this phosphorylation event is crucial for centriole formation in C. elegans embryos. Our results lead us to conclude that phosphorylation of the evolutionarily conserved protein SAS-6 is critical for centriole formation and thus for faithful cell division. Our most significant finding in human cells pertained to the role of CPAP in centriole elongation. Nor mally, the new centriole elongates to reach the same size as that of the old one. The mechanisms that govern elongation of centrioles and their potential relevance for cell division were not known prior to our work. In the course of this project, we demonstrated that overexpression of the SAS-4-related protein CPAP results in the formation of abnormally long centrioles in human cells, which eventually leads to the assembly of a multipolar spindle and defective cell division. Overall, these findings revealed that centriole length must be carefully regulated to ensure accurate cell division. Prof. Dr Pierre Gönczy Institut suisse de recherche expérimentale sur le cancer (ISREC) Faculté des sciences de la vie EPF de Lausanne (EPFL) SV 1526 Station 19 CH-1015 Lausanne Phone +41 (0)21 693 07 11 pierre.gonczy@epfl.ch Grassi Fabio Synergy between oncogenic Notch and pre-t-cell receptor (pre-tcr) signaling microdomains in leukemogenesis (OCS 01933-08-2006) T-cell acute lymphoblastic leukaemia (T-ALL) is a malignant disease of thymocytes (the cell in the thymus that normally differentiates into a circulating T lymphocyte) that preferentially affects children with variable prognosis. The variable prognosis is determined by the heterogeneity of the molecular alterations involved in the initiation and progression of the disease. This disease also received attention because children cured with gene therapy for hereditary immunodeficiency three years later developed T-ALL, which was determined by the virus used to correct the genetic defect. The long latency of the disease demonstrates the requirement of successive multiple molecular alterations (after the original one determined by virus integration into a particular region of the patient genome) for T-ALL development. The strength of the therapy used in T-ALL is based on the risk of relapsing disease, which is determined by the nature of the molecular alterations responsible for the disease. Thus it is important to thoroughly characterize these molecular alterations and find new targets for T-ALL therapy. In refractory subjects, intensification of existing treatments is unlikely to raise cure rates substantially and will instead increase treatment-related mortality and the risk of second cancers. Leukaemic cells are characterized by uncontrolled proliferation, which at least in part depends on concentration of particular proteins that induce (e.g. signal) cell proliferation into specific plasma membrane microdomains. We studied and characterized signalling by CD3 chains upon their deliberate diversion out of glycosphingolipidenriched microdomains. To this end we used a modified version of calnexin (a chaperone protein normally residing in the endoplasmic reticulum, ER, and associated with

CD3 chains in thymocytes) in which the ER retention signal was removed to allow delivery of calnexin and associated proteins to the plasma membrane. Mutant calnexin isoforms, either palmitoylated or not or with different cytoplasmic tails, were used to deliver CD3 to glycosphingolipid-enriched microdomains or plasma membrane or endosomes. Our study demonstrated that diversion of signalling complexes active in the generation of leukaemia in distinct signalling-incompetent domains of the plasma membrane significantly attenuated cell proliferation. Therefore, therapeutic strategies aimed at destabilizing glycosphingolipid-enriched signalling-competent plasma membrane microdomains might help in controlling proliferation of T-ALL cells. Dr. Fabio Grassi Istituto di ricerca biomedica (IRB) Via Vincenzo Vela 6 CH-6500 Bellinzona Phone +41 (0)91 820 03 23 Fax+41 (0)91 820 03 05 fabio.grassi@irb.unisi.ch Hall Michael N. Proteomic analysis of the cancerpromoting mtor pathway (KLS 01991-02-2007) The target of rapamycin is an atypical Ser/Thr kinase that positively regulates cell size, proliferation and cell motility in all eukaryotic organisms. TOR forms two functionally distinct multiprotein complexes, TORC1 and TORC2, which are conserved from yeast to human. Nutrients activate mammalian TOR (mtor) complex 1 (mtorc1), whereas growth factors activate mtorc1 and mtor complex 2 (mtorc2). Raptor and rictor are essential components of mtorc1 and mtorc2, respectively. Importantly, mtor also promotes tumourigenesis by as yet incompletely understood mechanisms. The finding that some tumours respond to the rapamycin or its analogues (rapalogues) underscores a role of mtor in tumourigenesis. Despite in-depth knowledge of the mechanisms by which TOR exerts its control of transcription, translation, ribosome biogenesis, and autophagy, very few direct mtor targets have been identified. Recently, we set out to find novel TOR targets by functional proteomics. Conceptually, we grew cells in a medium containing isotopically labelled amino acids ( heavy culture) and mixed cell extracts in a 1:1 ratio with those from normally grown cells ( light culture). The extracts were digested and phosphopeptides were enriched by way of immobilised metal affinity chromatography (IMAC/TiO2) and the phosphopeptides were measured in a high-resolution mass spectrometer. Because TOR possesses kinase activity, potential TOR targets can be detected by a decreased extent of phosphorylation following inhibition of TOR or disruption of the TOR complexes. We first established the proteomics workflow in the simple eukaryote S. cerevisiae. In this study we were able to quantitate approximately 2,400 phosphorylation events. Interestingly, the study revealed that yeast TORC1 controls phosphorylation of the regulatory subunit of camp-dependent protein kinase A (PKA), suggesting that TORC1 controls PKA toward some substrates. The main goal of our studies, however, was to identify novel targets of mammalian TOR. To distinguish between mtorc1- and mtorc2-specific phosphorylation, we specifically deleted Raptor or Rictor using an inducible gene knockout system in mouse embryonic fibroblasts (MEFs). We detected 4,584 phosphorylation sites on 1,398 proteins and identified 26 novel mtor effectors. Kinasemotif analysis revealed that mtor-dependent phosphorylation target sites comprise the pser/thr-pro and Arg- X-X-pSer motifs. These results suggest that mtor phosphorylates its novel effectors directly or via AGC kinase activation. We then compared the biological properties of all novel mtor effectors and identified several functional clusters. Many of the novel mtor effectors are overexpressed in cancer or linked to metabolic disorders. Thus, mtor regulates a large and diverse set of effectors to ultimately control cell growth and aging. Prof. Dr. Michael N. Hall Departement Biozentrum Universität Basel Klingelbergstrasse 50/70 CH-4056 Basel Phone +41 (0)61 267 21 50 Fax +41 (0)61 267 21 59 m.hall@unibas.ch Heim Markus Hermann Hepatocarcinogenesis in chronic hepatitis C (OCS 02192-02-2008) Background Chronic hepatitis C (CHC) is a major cause of liver disease worldwide and a risk factor for cirrhosis and hepatocellular carcinoma (HCC). Regardless of its aetiology, cirrhosis is a major clinical risk factor for HCC, and indeed, hepatitis C virus (HCV) associated HCC generally develops in patients with cirrhosis. There is also evidence for HCV specific tumourigenic pathways, mainly involving HCV core and NS5A proteins. However, the molecular pathways responsible for HCV induced hepatocarcinogenesis have not yet been characterized. A potential tumourigenic pathway could involve protein phosphatase 2A (PP2A) and protein arginine methyltransferase 1 (PRMT1), since both enzymes are dysregulated in chronic hepatitis C and both enzymes have been involved in chromatin remodelling and DNA damage repair. Aim The aim of the studies was to elucidate the role of PP2A overexpression and of PRMT1 inhibition for carcinogenesis. Methods We used cell lines that allow the inducible expression of hepatitis C virus proteins (UHCV57.3) and of the catalytic subunit of PP2A (UPP2A-C8) as well as Huh7.5 cells infected with recombinant cell culture-derived HCV (HCVcc) to study epigenetic histone modifications and DNA damage repair. We also investigated if the methyl group donor S-adenosyl-L-methionine (SAMe) could reverse the HCV induced changes. 71

72 Results The induction of viral proteins, the overexpression of PP2Ac or the infection of Huh7.5 cells with HCVcc resulted in an inhibition of histone H4 methylation/acetylation and histone H2AX phosphorylation in a significantly changed expression of genes important for hepatocarcinogenesis and inhibited DNA damage repair. These changes were partially reversed by the treatment of cells with the methyl-group donor S-adenosyl-L-methionine (SAMe). Conclusion The correction of defective histone modifications by S- adenosyl-l-methionine makes this drug a candidate for chemo-preventive therapies in patients with chronic hepatitis C who are at risk for developing hepatocellular carcinoma. Prof. Dr. Markus Hermann Heim Klinik für Gastroenterologie und Hepatologie Universitätsspital Basel Petersgraben 4 CH-4031 Basel Phone +41 (0)61 265 51 74 markus.heim@unibas.ch Hemmings Brian A. Role of protein kinase B (PKB/Akt) in cell transformation and cancer (OCS 01667-02-2005) Conserved from primitive metazoans to humans, the serine/threonine protein kinase B (PKB, also known as Akt) belongs to the AGC group of protein kinases and has emerged as a critical signalling molecule as a mediator of the phosphoinositide 3-kinase (PI3K) pathway. Activated upon PI3K signalling, PKB phosphorylates a wide range of substrates influencing diverse cellular and physiological processes, including cell cycle progression, cell growth and differentiation, cell survival/suppression of apoptosis, metabolism, angiogenesis and motility. As one of central node of signalling pathways, hyperactivation of PKB in most types of human cancers has been extensively studied towards an effective cancer therapy. Our research work led to the discovery of DNA-dependent protein kinase (DNA-PK) as a novel upstream kinase of PKB. We showed that PKB interacts and is phosphorylated by DNA-PK adjacent to DNA-double-strand breaks induced by g-irradiation, thus protecting the cell from DNA-damage-induced apoptosis. In addition, we also investigated the mechanisms of how activated PKB signalling inhibits p53 activity during DNA damage. We identified a novel PKB substrate, Twist1, a basic helix-loop-helix transcription factor that is phosphorylated by PKB on serine 42 (S42) when the cells are exposed to g-irradiation or genotoxic drug Adriamycin. S42 phosphorylation of Twist1 inhibits p53 activity. Mutation of S42 to alanine to prevent PKB-mediated phosphorylation sensitizes cells to DNA damage. Moreover, phosphorylation of Twist1 was demonstrated in various human cancer tissues, suggesting that this posttranslational modification ensures functional activation of Twist1 following promotion of survival during carcinogenesis. In parallel and in collaboration with other laboratories, we showed that the promyelocytic leukaemia (PML) tumour suppressor protein was activated by homeodomain-interacting protein kinase (HIPK2) in early stage responses to DNA damage. Overexpression of Twist1 has been reported in 21 cancer types including breast cancer, melanoma and prostate cancer, and correlates with poor prognosis in clinic. We showed that Twist1 phosphorylation on S42 promotes full epithelial-mesenchymal transition and this modification is essential for breast cancer metastasis to the lung in a mouse model. Furthermore, 1,532 invasive breast tumour samples were examined and revealed Twist1 phosphorylation in over 90 % of these tumour samples, including both invasive ductal and invasive lobular carcinomas, indicating an important regulatory role of Twist1 phosphorylation in cancer invasion and metastasis. As Twist1 does not seem to be active postnatally in human physiology but is deregulated during tumour progression, we are continuing to investigate if phosphorylated Twist1 may be a novel biomarker for tumour metastasis and a potential therapeutic target for metastatic cancers. Dr. Brian A. Hemmings Friedrich Miescher Institut für biomedizinische Forschung (FMI) Maulbeerstrasse 66 CH-4058 Basel Phone +41 (0)61 697 48 72 Fax +41 (0)61 697 39 76 brian.hemmings@fmi.ch Hemmings Brian A. The role of human protein kinase NDR in cell morphogenesis, cell division, growth control and cancer (OCS-01942-08-2006) The NDR proteins family is a group of serine/threonine kinases that is conserved from yeast to man. They are members of the AGC kinase family and include molecules such as LATS, Cbk1, Orb6, Cot-1 and Dbf2. In budding yeast Dbf2 is an integral part of the mitotic MEN network, and Cbk1 is required for the regulation of morphological changes. Recent genetic studies have resulted in the isolation of various important factors controlling these processes. Significantly, these studies have also shown that the yeast counterparts of NDR interact with Mob1 and Mob2. These interactions are very important, since they are essential for the activity and biological function of these yeast kinases. Based on these findings our laboratory could show that the interaction between human MOB1 (hmob1) and MOB2 (hmob2) with the human NDR and LATS kinases plays a decisive role. By testing mutants of hmob1, hmob2, NDR and LATS, we observed that a direct interaction between hmob1 and NDR or LATS is needed to ensure activation of these kinases, while the interaction of

hmob2 with NDR results in inhibition of kinase activity. Furthermore, we could define the nature of the kinase responsible for the activating phosphorylation of NDR kinase. Interestingly, we found that the MST1 kinase is the main player. After we showed that human NDR plays a crucial role in centrosome biology, we described that this function is controlled by MST1. Moreover, our research revealed that MST1/NDR signalling also plays a role in the regulation of normal cell death. Therefore, our studies demonstrated that two important cell biological processes are regulated by NDR kinases. On the one hand, NDR plays a role in the accurate duplication of centrosomes, which can play a critical role in the correct distribution of DNA information. On the other hand, we could show that NDR is required for accurate execution of programmed cell death. Since both processes can play a role in the development of cancer, our data suggest that NDR kinases are very likely to play an important role in cancer. In this context it is noteworthy that we recently defined a function for NDR kinases in normal cell multiplication. By down-regulating NDR expression using RNAi technology we found that human cells require NDR to progress into S- phase of the cell cycle. Furthermore, we have inactivated the NDR1 and NDR2 genes in the mouse in order to allow studies of the physiological functions of NDR kinases. Significantly, NDR1 knock-out animals developed T-cell lymphomas, indicating that NDR kinases can play a role as tumour suppressor proteins. The analysis of NDR2 knockout mice is currently ongoing to obtain the full spectrum of the physiological functions that play a role in cancer development. Dr. Brian A. Hemmings Friedrich Miescher Institut für biomedizinische Forschung (FMI) Maulbeerstrasse 66 CH-4058 Basel Phone +41 (0)61 697 48 72 Fax +41 (0)61 697 39 76 brian.hemmings@fmi.ch Herr Winship HCF-1 regulation of genomic stability during cell division (OCS 02047-02-2007) We studied the function of a protein called HCF-1 that controls human cell proliferation and is important for the correct distribution of the genome during cell division. The studies showed that HCF-1 associates with a large number of cellular proteins, many of which are involved in the modification of chromatin the integrated structure of DNA and proteins responsible for the regulation of gene expression and the proper chromosome replication and segregation during cell division. These studies also showed that a process of proteolytic maturation specific to HCF-1 is achieved by the enzyme O-linked N-acetylglucosamine transferase (OGT), for which the only known activity until now was protein glycosylation. Given that OGT and glycosylation are linked to metabolism, these studies demonstrated a nexus between metabolism and cell-cycle regulation. Objectives This project had three objectives: 1) to understand the roles of HCF-1 in the cell cycle; 2) to uncover the mechanisms of HCF-1 proteolytic maturation; and 3) to elucidate how the two HCF-1 subunits can influence one another. Method and process To realize the first objective, proteins associated with HCF-1 were identified via biochemical purification and mass spectroscopy, followed by bioinformatic analysis as well as studies of known HCF-1 protein associations by molecular analysis. The second objective was realized by (i) biochemical purification; (ii) directed analysis of HCF-1 modifications linked to proteolysis of the protein; and (iii) determination of OGT activity. For the last objective we analyzed the cell-cycle defects in particular mitosis resulting in the presence of HCF-1 mutant proteins. Results The analyses of HCF-1-associated proteins showed that HCF-1 associates with a large number of protein complexes that regulate chromatin function. The analysis of HCF-1 activity in promoting DNA replication during the S phase of the cell cycle showed that the association of HCF-1 with E2F1, a transcription factor crucial for entry into S phase, and the family of mixed-lineage leukaemia (MLL) histone methytransferases is important not only to activate S phase but also to activate apoptosis following DNA damage or inappropriate activation of E2F1. Our studies on the proteolytic maturation of HCF-1 and the functional interaction between the resulting subunits demonstrated that the enzyme OGT responsible for protein glycosylation is unexpectedly also directly involved in the proteolysis of HCF-1. The consequence of HCF-1 cleavage by OGT is that the N-terminal HCF-1 subunit is glycosylated such that it does not repress the activities of the C-terminal subunit in M phase. These results reveal a nexus between the covalent modification and proteolysis of a protein and suggest an interaction pathway between metabolism and the regulation of cell proliferation. Prof. Dr Winship Herr Centre intégratif de génomique (CIG) Faculté de biologie et de médecine Université de Lausanne Génopode Building CH-1015 Lausanne 15 Phone +41 (0)21 692 39 22 Fax +41 (0)21 692 39 25 winship.herr@unil.ch 73

74 Hübscher Ulrich Repair of oxidation damages in DNA: DNA synthesis over lesions by posttranslationally modified human DNA polymerase lambda (OCS-01996-02-2007) The maintenance of genetic stability is of crucial importance for any form of life. Prior to cell division in each mammalian cell, the process of DNA replication must faithfully duplicate the three billion bases with an absolute minimum of mistakes. On the other hand, DNA itself is highly reactive and is constantly attacked by endogenous factors and is also easily altered by intracellular processes such as oxidation. 7,8-dihydro-8-oxoguanine (8-oxo-G) is recognized as one of the most important oxidative DNA lesions because of its prevalence in DNA and its mutagenic potential in cells. It has been estimated that the steady-state level of 8-oxo-G lesions is about 10 3 per cell in normal tissues and up to 10 5 lesions per cell in cancer tissues. All human DNA polymerases (DNA pols) studied so far show significant error-prone bypass of 8-oxo-G, since they preferentially incorporate an adenine opposite an 8-oxo-G instead of the correct cytosine. This would lead to subsequent G-C to T-A transversion mutations with the consequence of cell transformation and eventually leading to cancer. Findings and relevance We reconstituted with human proteins a completely errorfree bypass pathway for an 8-oxo-G lesion located in codon 13 of the human HRAS gene. Specialized DNA pols are required for lesion bypass in human cells. Auxiliary factors play an important but so far poorly understood role. A major and specific effect was found for 8-oxo-G bypass with DNA pol l. PCNA and RP-A allowed correct incorporation of dctp opposite a template 8-oxo-G 1200-fold more efficiently than the incorrect datp by DNA pol l. Our findings suggest a novel accurate mechanism to reduce the deleterious consequences of oxidative damage. In addition, they point to an important role for PCNA and RP-A in determining a functional hierarchy among different DNA pols in lesion bypass. New data We identified several phosphorylation sites of DNA pol. Experiments with phosphorylation-defective mutants suggest that phosphorylation of T553 is critical for maintaining DNA pol stability, since it is targeted to the proteasomal degradation pathway via ubiquitination unless this residue can be phosphorylated. In particular, DNA pol is stabilized during cell cycle progression in late S and G2 phase. This likely enables DNA pol to properly conduct repair of damaged DNA during and after S phase. Prof. Dr. Ulrich Hübscher Institut für Veterinärbiochemie und Molekularbiologie Universität Zürich Winterthurerstrasse 190 CH-8057 Zürich Phone +41 (0)44 635 54 72 Fax +41 (0)44 635 68 40/59 04 hubscher@vetbio.uzh.ch Huelsken Joerg Role of inflammation in Wnt mediated tumorigenesis (OCS 01838-02-2006) A large amount of data demonstrates the impact of the Wnt pathway on the intrinsic ability of the tumour cells to proliferate and survive, thereby promoting tumourigenesis. We have now obtained data suggesting a novel mechanism in which Wnt signalling promotes tumour formation by modulating the extrinsic milieu and in particular influencing immune cell recruitment and activation in the tumour microenvironment. Aim of the study We had recently studied a skin tumourigenesis model that relies on chronic inflammation for tumour promotion and outgrowth. In these skin tumours, we found that inhibition of Wnt pathway signalling by b-catenin depletion completely abolishes tumour formation (Malanchi et al., Nature 2008;452:650). The aim of the present study was to understand the crucial function of Wnt signalling at the onset of skin tumour formation. Methods The study was mainly conducted using in vivo models and chemical tumourigenesis which rely on chronic inflammation for tumour initiation. Orthotopic transplantation techniques were used to clarify the ability of tumour cells to grow when placed within different microenvironments. Results We found that b-catenin mutant skin shows a significant difference in the inflammatory reaction induced within the dermis. Using immunohistochemistry and fluorescentactivated cell sorting we were able to identify the immune cell subpopulation that was affected by this block of Wnt signalling. To link this observation with tumour initiation, transplantation and reconstitution experiments were performed using a combination of normal skin cells, keratinocytes and tumour cells. When tumour cells were placed in an immunocompromised environment characterized by dampened inflammatory activity, these tumour cells were not able to initiate tumourigenesis. On the other hand, forced stimulation of the inflammatory cascade was found to overcome the lack of Wnt signalling and could promote tumour formation. Detailed analysis revealed that keratinocytes are major contributors to this early inflammatory response, since they release a variety of stimulatory molecules that recruit immune cells. To this end, transcriptional profiles of activated keratinocytes were determined to discover potential mediators of this Wnt mediated response. This was followed by functional validation of some of these signals, which helped to identify the relevant ones. Notably, this suggests that the crucial crosstalk between resident cells and recruited immune cells is in part mediated by Wnt signalling. Moreover, we found that the same pathway is also involved intrinsically in immune cells to allow for chemoattraction and activation in response to pro-inflammatory stimuli. In combination, these data indicate a potent function of Wnt signalling in modulating the inflammatory response, which is fundamental in the initiation of cancer. Since the connection be

tween chronic inflammation and epithelial tumourigenesis is well established, this suggests that preventive treatment of risk patients should consider Wnt signalling as a new target. Prof. Dr Joerg Huelsken UPHUE Institut suisse de recherche expérimentale sur le cancer (ISREC) Faculté des sciences de la vie EPF de Lausanne (EPFL) SV 2823 (Bâtiment SV) Station 19 CH-1015 Lausanne Phone +41 (0)21 692 58 43 Fax +41 (0)21 652 69 33 joerg.huelsken@epfl.ch Hynes Nancy Characterisation of the role of PN-1 in breast cancer and its potential as a therapeutic target (KLS 02187-02-2008) Proteases mediate cancer cell invasion and metastasis via their ability to degrade the extracellular matrix surrounding the tumour. Extracellular serine protease inhibitors block the activity of many cancer-expressed proteases and have been considered to have cancer protective effects. However, it has been found that high levels of protease inhibitors, including protease nexin-1 (PN-1), as we show in the project supported by the Swiss Cancer League, correlate with poor patient prognosis, suggesting that these inhibitors have positive roles in cancer progression. Thus, our experiments were designed to test the role of PN-1 in a metastatic breast cancer model. Goal Based on our in silico analysis of PN-1 expression levels in >350 breast tumours, revealing that higher expression correlates with markers of poor clinical prognosis, the goal of our work was to uncover the mechanism whereby high levels of the serine protease inhibitor PN-1 contribute to breast cancer.

76 Methods and experimental approaches 1) In silico approaches were used to examine RNA expression levels of PN-1 in multiple primary breast tumours, to correlate PN-1 expression levels with clinical parameters, and to investigate the possibility that high PN-1 levels might have prognostic value in breast cancer. 2) Biochemical approaches were carried out with different ex vivo cultured cell lines to study the signalling pathways stimulated by treatment of cells with purified PN-1 protein. 3) In vivo tumour studies were performed to examine the effects of PN-1 ablation on the ability of a metastatic breast cancer model to form primary mammary tumours and to form lung metastases. Results In our work we used computational analyses to show that levels of the serine protease inhibitor PN-1 are significantly higher in high grade compared to low grade breast cancer. Using breast cancer models with low and high PN-1 levels we showed that PN-1 treatment of mammary tumour cells not expressing PN-1 stimulated ERK activity and matrix metalloproteinase-9 (MMP-9) production via low-density lipoprotein receptor-related 1 (LRP-1) binding. Moreover, shrna mediated ablation of PN-1 expression in PN-1 overexpressing mammary cancer cells had a strong negative impact on the ability of the cells to form lung metastases. Thus, our work uncovered a novel pathway, whereby the serine protease inhibitor PN-1, via LRP-1 binding LRP1, activates signalling pathways that stimulate MMP-9 upregulation and metastatic spread. Importantly, an analysis of 126 patients with breast cancer revealed that those whose breast tumours had elevated PN-1 levels had a significantly higher probability to develop lung metastases but not metastases to other sites, on relapse. These results suggest that PN-1 might become a prognostic marker in breast cancer. Prof. Dr. Nancy Hynes Friedrich Miescher Institut für biomedizinische Forschung (FMI) Maulbeerstrasse 66 CH-4058 Basel Phone +41 (0)61 697 81 07 Fax +41 (0)61 697 39 76 nancy.hynes@fmi.ch Janscak Pavel Study of the role of the human mismatch repair system in telomere metabolism (OCS 01730-08-2005) Telomeres are regions of repetitive DNA sequence at the ends of eukaryotic chromosomes that protect chromosome ends from being recognized as deleterious DNA double-strand breaks. In normal cells, telomeres get progressively shortened due to the inability of DNA polymerases to fully replicate DNA ends. Critically short telomeres generate chromosome end fusions that cause loss of replicative capacity, leading to senescence or apoptosis. Therefore, it is believed that telomere shortening is a determinant of cellular life span and acts as a tumour suppressor mechanism. Cancer cells escape from this type of control of cellular proliferation by activating a telomere length maintenance mechanism. A substantial number of cancers employ a recombination-based mechanism referred to as alternative lengthening of telomeres (ALT). In yeast cells lacking telomerase, a reverse transcriptase that can synthesize telomeric DNA, inactivation of the proteins involved in the initiation of mismatch repair (MMR), such as Msh2 and Mlh1, promotes cellular proliferation in a manner dependent on homologous recombination. The aim of this project was to explore the role of the MMR system in telomere metabolism in human cells. The project utilized different molecular and cell biology methods in combination with biochemical techniques. Using various human cell lines, we examined whether the MMR proteins are localized at telomeres and whether depletion of these proteins has an effect on telomere integrity. We found that the MMR proteins MSH2 and MLH1 were associated with telomeres in ALT-positive cancer cells but not in ALT-negative cells. We also found that MSH2 and MLH1 formed a complex with the Werner syndrome helicase/exonuclease (WRN), which plays a critical role in the maintenance of telomere integrity. Moreover, our biochemical experiments with purified proteins indicated that the MSH2/MSH3 and the MSH2/MSH6 heterodimers could enhance WRN-mediated unwinding of synthetic DNA structures that resemble recombination intermediates. Finally, analysis of recombination events at telomeres in a human embryonic kidney cell line with inducible expression of MLH1 revealed an elevated frequency of telomeric sister chromatid exchanges upon inhibition of MLH1 expression. Defects in a subset of MMR genes including MSH2, MSH3, MSH6, MLH1 and PMS2 are associated with hereditary non-polyposis colorectal cancer. Our findings have implications for understanding of the molecular events underlying the tumourigenic process initiated by the loss of mismatch repair capacity. Dr. Pavel Janscak Institut für molekulare Krebsforschung Universität Zürich Winterthurerstrasse 190 CH-8057 Zürich Phone +41 (0)44 635 34 70 pjanscak@imcr.uzh.ch

Lange Norbert Synthesis and evaluation of new water soluble polymeric photosensitizer prodrugs for photodynamic therapy (OCS 01948-08-2006) Despite our increasing understanding of the mechanisms and pathways that lead to the development of cancer, in most cases our first line treatment options against this devastating disease have remained essentially unchanged for decades. At least every second of us has heard about or seen the dramatic traces that these conventional cancer therapies, including surgery, radiation therapy and chemotherapy, leave on patients that have to undergo such treatments with respect to side effects and quality of life. Therefore, one of the greatest challenges for scientists working in applied cancer research is to find new alternatives that can replace or complement these therapeutic approaches. One alternative that has attracted considerable attention in the past is photodynamic therapy (PDT). It is based on the administration of a photosensitizer (PS) that selectively accumulates in tumour tissue. Upon irradiation with light the photosensitizer triggers numerous photochemical processes that ultimately lead to the destruction of the tumour tissue. Interestingly, the action of PDT is confined to areas in which the PS, light and oxygen are concomitantly present. Despite early clinical promise and repeatedly reported successful results, the further development of PDT was hampered by some intrinsic drawbacks of the PS itself. The aim of our study financed by Oncosuisse was the development and evaluation of PS that can be easily formulated, selectively accumulate in tumour tissue, are inactive until they encounter certain cancer-specific signals and are readily eliminated from the body in their native form. Our research was inspired by the observation that high local densities of PS lead to its inactivation. We therefore coupled multiple copies of PS to a polymeric carrier through a peptide linker that can be specifically cleaved by proteases. Some of these enzymes that digest proteins are upregulated in tumours and play key roles in the invasion and metastasis of cancer. In initial studies we showed that these PS prodrugs depend on the number of PSs per polymer up to 700 times less active than in their free form. In absence of light and/or the target protease the compounds were void of any photoactivity. We then designed PS prodrugs that we specifically activated by urokinase-like plasminogen activator, upregulated in many kinds of cancer including breast, colon, and prostate cancer. In vitro, we showed that cells expressing this protease are effectively eliminated through PDT in the presence of the specific prodrug but not by a control substance. Further, we demonstrated the specific activation of our compounds in an experimental animal model for prostate cancer. In subsequent studies, we were able to optimize the pharmacokinetics of these newly developed PS prodrugs. Thanks to the financial support of Oncosuisse, we are able to prepare PS prodrugs specifically designed for any protease and to cure mice inoculated with highly invasive prostate cancer through PDT. These findings might now well lead to a new approach for the treatment of confined prostate cancer, without known side effects of resection or brachytherapy. Prof. Dr Norbert Lange Laboratoire de pharmaceutique et de biopharmacie Section des sciences pharmaceutiques Université de Genève 30, quai Ernest-Ansermet CH-1211 Genève 4 Phone +41 (0)22 379 33 35 norbert.lange@unige.ch MacDonald Hugh Robson The role of protooncogenes in hematopoietic and cancer stem cells (OCS 01863-02-2006) The c-myc gene was the first member of the Myc family to be discovered thirty years ago. In mammals, the Myc family of transcription factors is comprised of three structurally similar proteins: c-myc, N-Myc and L-Myc. These proteins share the same biological properties and exert the same functions but they are usually mutually exclusively expressed, with only one member of the family highly expressed in each particular cell type. Due to its predominant role in tumour development, a comprehensive understanding of the mechanisms that regulate Myc proteins in normal tissues is necessary to develop novel anti-cancer therapies. Our laboratory recently demonstrated that c-myc elimination leads to the accumulation of haematopoietic stem cells (HSCs). HSCs are responsible for the lifelong production of all functional blood cells. They are defined by their capacity to produce other stem cells (self-renewal) as well as cells called progenitors, which in turn generate all types of differentiated blood cells (B and T lymphocytes, red blood cells, monocytes and others, all specialized in specific functions). HSC deregulation participates in numerous haematological pathologies such as anaemias, leukaemias and lymphomas. To better understand the role of the Myc family members in HSCs, we chose to first systematically characterize where c-myc, N-Myc and L-Myc are expressed at each step of haematopoietic development, from HSCs to fully mature blood cells. By doing so we uncovered the first example of an adult cell that produces equivalent amounts of c-myc and N-Myc transcripts: the most immature HSCs. As such, HSCs represent an excellent model to study the extent of functional redundancy between c- Myc and N-Myc. We thus generated a series of genetically-modified mouse strains that express different levels 77

78 of c-myc and/or N-Myc and demonstrated for the first time in vivo that these two proteins exert the same functions but with different efficiencies. Furthermore, when analyzing mice in which the c-myc and N-Myc genes were simultaneously eliminated (double knock-out), we uncovered that in order to survive, HSCs must repress granzyme B, an enzyme usually used by the innate immune system to eliminate cancer or virus-infected cells. In the absence of both c-myc and N-Myc, HSC fail to silence granzyme B, which is then activated, resulting in rapid cell death. Finally, the investigation of our c-myc/n-myc double knock-out model indicated that general Myc activity, contributed by the combined action of c-myc and N-Myc, controls several other aspects crucial to HSC function, in particular their self-renewal and differentiation into haematopoietic precursors. In summary, our genetic dissection of the individual and common contributions of c-myc and N-Myc considerably improved our understanding of the physiological roles of the Myc family of proteins and opens new avenues for the treatment of several haematopoietic pathologies. Dr Hugh Robson MacDonald Centre Ludwig de recherche sur le cancer CH-1066 Epalinges Phone +41 (0)21 692 59 89 Fax +41 (0)21 692 59 95 hughrobson.macdonald@licr.unil.ch Moradpour Darius Development of a model system to study coinfection by hepatitis B and C viruses the major causes of hepatocellular carcinoma (OCS 01762-08-2005) Background and aim Hepatocellular carcinoma (HCC) is one of the most common malignant tumours worldwide. A rise in the incidence of and mortality from HCC has been documented in most industrialized countries, and the increase is expected to continue for at least the next two decades. Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) account for well over 80 % of HCC cases worldwide. Coinfection with HBV and HCV is common due to shared modes of transmission. However, the virological and molecular aspects of HBV-HCV coinfection are poorly understood. While the development of cirrhosis and HCC is more frequent and accelerated in HBV-HCV coinfection, an inverse relationship in the replicative levels of the two viruses has been noted, suggesting direct or indirect viral interference. Understanding the mechanisms of viral interference in HBV-HCV coinfection is likely to yield important clues to the pathogenesis of viral persistence and liver disease and, thereby, the development of HCC. How ever, interactions between HBV and HCV have been difficult to study because of the lack of appropriate model systems. On this background, the aim of this project was to establish a model system in which both viruses and their interactions can be studied in a well-characterized and meaningful cellular context. Experimental design and methods A tetracycline-regulated gene expression system, allowing the inducible expression of a replication-competent HBV construct, as well as selectable HCV replicons and cell culture-derived HCV (HCVcc) were used to establish Huh-7 human HCC cell lines replicating both viruses simultaneously. Independent inducible cell lines as well as control cell lines inducibly expressing the green fluorescent protein were established, because significant clonal variation in HCV RNA replication and susceptibility to HCVcc infection had been noted in the past. Results Three successive transfection and selection steps allowed the establishment of Huh-7 cell lines replicating HBV and HCV RNA. In these cell lines, it is possible to control the expression of HBV proteins, HBV replication and infectious viral particle formation by the concentration of tetracycline in the culture medium while HCV proteins are expressed and HCV RNA replicated constitutively. In this system, both viruses were found to replicate in the same cell without overt interference. Specific inhibition of one virus did not affect the replication and gene expression of the other. Further, cells harbouring replicating HBV could be infected with HCVcc, arguing against superinfection exclusion. Finally, cells harbouring replicating HBV supported efficient production of infectious HCV. Taken together, these results demonstrate that HBV and HCV can replicate in the same cell without evidence for direct interference in vitro. Conclusions and perspectives We established a novel model system allowing the study of HBV-HCV coinfection under highly reproducible conditions in vitro. Our results demonstrate a remarkable lack of direct interference between HBV and HCV, implying that the two viruses rely on distinct and non-competing sets of host factors for their replication. These observations suggest that the viral interference observed in coinfected patients is probably due to indirect mechanisms mediated by innate and/or adaptive host immune responses. Further study of such interactions may provide new clues to the pathogenesis and clinical management of HBV-HCV coinfection and HCC. Prof. Dr Darius Moradpour Service de gastro-entérologie et d hépatologie Centre hospitalier universitaire vaudois (CHUV) Université de Lausanne Rue du Bugnon 44 CH-1011 Lausanne Phone +41 (0)21 314 47 14 Fax +41 (0)21 314 47 18 darius.moradpour@chuv.ch

Nägeli Hanspeter Regulation of nucleotide excision repair by protein modifiers (KLS 01827-02-2006) The frequency of skin cancer due to sunlight exposure is increasing dramatically. The ultraviolet (UV) radiation of sunlight induces damage in the genome by causing the crosslinking of adjacent DNA bases. According to the type of chemical link, these UV lesions are known as cyclobutane dimers or 6,4 photoproducts. They lead to genetic abnormalities and result in cancer unless they are readily removed by DNA repair. This removal of UV crosslinks from the genome is carried out by a multi-component DNA repair system generally known as nucleotide excision repair. However, this DNA damage excision machinery faces the important problem that the cellular DNA substrate is tightly packaged in chromatin, raising the question of how UV lesions may be detected in such a poorly accessible environment. Another problem is that cyclobutane dimers cause minimal changes of the DNA structure, and therefore, this particular type of crosslink is poorly recognized by XPC protein, which is the initial damage sensor component of the DNA repair machinery. In the frame of our research project, we used cell biology methods to analyze the dynamic assembly and disassembly of active repair complexes in the chromatin context. This approach led us to discover two novel regulatory mechanisms that coordinate the DNA repair of UV lesions in human skin cells. As a master regulator in both control systems we have identified DDB2, a previously enigmatic factor known on the basis of its binding preference for UV-damaged DNA but whose function in the DNA damage response remained unclear. We discovered that DDB2 is able to inspect the cellular chromatin to search for highly accessible sites and demarcate these hotspots for DNA repair activity. For that purpose, DDB2 recruits an enzyme complex that mediates the modification of the XPC sensor protein with ubiquitin residues. These attached ubiquitin modifiers mediate the retention of XPC protein at DNA repair hotspots, thus preventing its futile migration to more densely packed chromatin that is refractory to DNA repair. By this mechanism, DDB2 ensures the fast repair of DNA sites that are actively engaged in critical cellular processes, thus providing more time for the long-term and slow repair of less accessible chromatin sites. Independently of ubiquitin modifiers, we found that DDB2 is also able to exert a lever action on the DNA double helix to allow for the docking of the XPC sensor to the otherwise unrecognizable cyclobutane dimers and thus initiate their repair. In summary, our results show that DDB2 is a master organizer that optimizes the spatiotemporal distribution of DNA repair activity in the chromatin of human skin cells. In future experiments, we will test how vitamins, UV filters, antioxidants and other ingredients of cosmetics or sunscreens influence the quantity and function of DDB2 in human cells. Knowledge of these regulatory systems provides a rational basis for preventive interventions to increase the efficiency and precision of DNA repair and hence to reduce the risk of skin cancer. Prof. Dr. Hanspeter Nägeli Institut für Veterinärpharmakologie und -toxikologie Universität Zürich Winterthurerstrasse 260 CH-8057 Zürich Phone +41 (0)44 635 8763 naegelih@vetpharm.uzh.ch Ochsenbein Adrian F. Immunosurveillance of chronic myeloid leukemia in mice (OCS 01627-02-2005) Chronic myelogenous leukaemia (CML) is a malignant clonal myeloproliferative disease arising from a haematopoietic stem cell expressing the BCR/ABL fusion protein. CML is characterized by a chronic phase lasting for several years. During this time period, immune responses co-exist with the CML and probably control the disease. Eventually CML progresses from the chronic phase to terminal blast crisis. This might be due to failure in immunosurveillance. We identified peripheral and central tolerance mechanisms that impair the immunosurveillance of CML and contribute to disease progression in a murine CML model. To this end, we transduced bone marrow cells from donor mice with a retroviral construct that expresses the oncogene BCR/ABL and transferred these cells to recipient mice. We found that CML-specific CTLs were functionally impaired. CTL did not produce effector cytokines, did not proliferate after antigenic stimulation and displayed very limited cytolytic function. This functional impairment of CTL is termed exhaustion. CTL exhaustion has been attributed to the signal transduction of different inhibitory receptors such as PD-1. Indeed, CTL exhaustion in CML was mediated by the PD 1/PD L1 interaction. Blocking PD-1 signal transduction by using PD-1-deficient recipient mice or by administration of apd-l1 antibody reversed CML-specific T cell tolerance, and the time to disease progression was increased. In addition, PD-1 was upregulated on CD8 + T cells from CML patients, suggesting that this inhibitory pathway may also be of importance in the regulation of CML-specific CTLs in humans. The BCR/ABL fusion protein provides novel and potentially immunogenic tumour-specific antigens. The leukaemia BCR/ABL expressing stem cell differentiates to different cell populations including professional antigen-presenting dendritic cells (DC). BCR/ABL-expressing DCs were found in various organs. However, BCR/ABL-expressing DCs failed to efficiently induce leukaemia-specific T cell responses due to low DC maturation and impaired migration to secondary lymphoid organs. Moreover, we demonstrated that BCR/ABL-expressing DCs preferentially migrated to the thymus where they induced a deletion of leukaemia-specific CD8 + T. 79

80 In summary, this work improves our understanding of the contribution of the immune system in controlling CML. Functional impairment of CML-specific CTLs by PD-1 signalling and central-deletion of leukaemia-specific CTL by BCR/ABL-expressing DCs in the thymus contribute to the escape of CML from immunosurveillance. These findings open up new possibilities for immunotherapies against CML. Prof. Dr. Adrian Ochsenbein Universitätsklinik für medizinische Onkologie Inselspital Freiburgstrasse 10 CH-3010 Bern Phone +41 (0)31 632 84 42 Fax +41 (0)31 632 41 19 adrian.ochsenbein@insel.ch Orend Gertraud Analysis of a potential oncogenic function of tenascin-c and tenascin-w in colon cancer (OCS 01875-02-2006) The extracellular matrix (ECM) molecule tenascin-c, which is highly expressed in most solid cancers, plays an important role in angiogenesis, tumour proliferation and progression and correlates with signs of bad prognosis in several cancers. Tenascin-C is one of a few genes with predictive value in breast cancer metastasis to the lung. Its high expression also correlates with tamoxifen resistance in patients with breast cancer. Recently, an antibody targeting tenascin-c was used to stimulate the immune system, thus destroying the experimental breast cancer. Thus, tenascin-c plays a crucial role in cancer that is incompletely understood at the mechanistic level. Our recent published and unpublished research contributed to the understanding of the mechanisms of tenascin- C-induced tumour progression. We identified two independent mechanisms by which tenascin-c inhibits cell adhesion to fibronectin, another ECM molecule with a high expression in cancer tissue. Tenascin-C competes binding of syndecan-4, an essential coreceptor of integrin alpha5 beta1, to fibronectin, thus promoting tumour cell proliferation. Tenascin-C induces expression and signalling of endothelin receptor type A, which may be instrumental in cancer progression by stimulating angiogenesis and epithelial-to-mesenchymal transition. We also described that reduced cell adhesion by tenascin-c serves as a prerequisite for growth factors to trigger tumour cell migration. In particular, lysophosphatidic acid together with platelet derived growth factor stimulated migration on a tenascin-c substratum, which may be relevant in glioma progression and in the neuronal stem cell niche, which are places that exhibit a high expression of tenascin-c and of both molecules and their receptors. This information could be important for refining tenascin- C expression as diagnostic factor in cancer. We discovered that tenascin-c activates oncogenic Wnt and endothelin receptor type A signalling. We were also involved in a study where activation of Toll-like receptor 4 signalling by tenascin-c was found to be crucial in rheumatoid arthritis. In a xenograft model where minced human colon cancer tissue had been injected into immune-compromised mice we had analysed expression and organization of tenascin- C and tenascin-w in the arising tumours. We observed that both tenascins were highly expressed with eventual overlapping patterns. The organization of both tenascins into matrix tracks together with other matrix molecules was very similar in the xenograft tumour compared to the human tumour, suggesting that at least some characteristics of the original cancer can be preserved in the xenograft model. Dr Gertraud Orend Institut national de la santé et de la recherche médicale (INSERM) Unit 682 3, avenue Molière F-67200 Strasbourg France Phone +33 (0)3 88 27 53 55 Fax +33 (0)3 88 26 35 38 gertraud.orend@inserm.u-strasbg.fr Pabst Thomas The myeloid key transcription factor CEBPA and the pathophysiology of acute myeloid leukemia (OCS 01833-02-2006) In the focus of our current understanding of the pathogenesis of acute myeloid leukaemia is the leukaemic stem cell transformed from normal pluripotent blood precursor cells. Moreover, these leukaemic stem cells also represent the goal of therapeutic efforts. Deregulation of a small group of transcription factors seems to be involved in the transformation from normal precursor cells to leukaemic stem cells. In patients with acute myeloid leukaemia (AML), such transcription factors are often mutated or their expression is altered. A prominent example is the transcription factor CEBPA, which is necessary for the normal maturation of blood precursor cells towards mature white blood cells (granulocytes). In a substantial percentage of patients with AML, the CEBPA gene is mutated. In the present research project, we are analyzing a certain type of CEBPA mutations in patients with AML. We hope that the results will reveal the mechanism of how this type of CEBPA mutations contributes to the development of the disease in these patients. Prof. Dr. Thomas Pabst Universitätsklinik für medizinische Onkologie Inselspital CH-3010 Bern Phone +41 (0)31 632 41 15 Fax +41 (0)31 632 41 19 thomas.pabst@insel.ch

Peter Matthias Regulation of genome stability by Rtt101p/cullin4-based E3-ubiquitin ligases in yeast and mammalian cells (OCS 02189-02-2008) Cullin 4 (Cul4)-based ubiquitin ligases have emerged as critical regulators of DNA replication and repair. Over 50 Cul4-specific adaptors (DCAFs) have been identified and are thought to assemble functionally distinct Cul4 complexes. Using a live-cell imaging-based RNAi screen, we analyzed the function of DCAFs and Cul4-linked proteins and identified specific subsets required for progression through G1 and S-phase. We discovered C6orf167/ Mms22L as a putative human orthologue of budding yeast Mms22, which together with the cullin Rtt101 regulates genome stability by promoting DNA replication through natural pause sites and damaged templates. Loss of Mms22L function in human cells results in S-phase-dependent genomic instability characterized by spontaneous double strand breaks and DNA damage checkpoint activation. Unlike yeast Mms22, human Mms22L does not stably bind to Cul4 but is degraded in a Cul4-dependent manner and upon replication stress. Mms22L physically and functionally interacts with the scaffold-like protein Nfkbil2 that co-purifies with histones, several chromatin remodelling and DNA replication/repair factors. Together, our results strongly suggest that the Mms22L-Nfkbil2 complex contributes to genome stability by regulating the chromatin state at stalled replication forks. Prof. Dr. Matthias Peter Institut für Biochemie ETH Zürich HPM G8 Schafmattstrasse 18 CH-8093 Zürich Phone +41 (0)44 633 65 86 Fax +41 (0)44 632 12 98 matthias.peter@bc.biol.ethz.ch Plückthun Andreas Tumor targeting of ErbB2 with designed ankyrin repeat proteins (OCS 02128-08-2007) In the last ten years, targeted tumour therapy has made a major leap forward, mainly due to improvements in the design and production of antibodies. However, despite the technological advances, targeting molecules such as antibodies, in particular as fusion proteins with toxic moieties, often suffer from unfavourable biophysical properties, expensive production and limited efficacy if used as monotherapy. Therefore, complementary molecular scaffolds are in high demand and the subject of intense research. We have developed a new class of binding molecules, termed designed ankyrin repeat proteins (DARPins) that display high affinities for their targets, outstanding biophysical properties and a wide range of targets, and they can be manufactured in bacteria in large amounts at low cost. We chose the ErbB2 receptor as a target tumour antigen. Overexpression of ErbB2 occurs in a broad range of human cancers, including up to 30 % of breast carcinoma, and high ErbB2 levels have been correlated with an aggressive metastatic tumour phenotype. Consequently, high expression of ErbB2 may be employed for tumour targeting, where the receptor is used as a cellular gate to convey therapeutic payloads into the tumour cells. Notably, the inhibition of tumour growth may be induced solely by the binding to the receptor in as much as ErbB2 is required for the proliferation of tumour cells. In order to achieve high treatment efficiency, we aimed to construct ErbB2-targeting molecules combining several favourable attributes. In the course of this project, we established an array of powerful methods for selection and maturation of the DARPin binders. By this means, a number of ErbB2-directed binders were selected and profiled for their efficiency to inhibit tumour growth in cell culture models. Several binders were further engineered by methods of molecular biology and computational molecular design, and the resulting molecules reached tumouristatic activity that surpassed the efficacy of the anti-erbb2 antibodies currently used in the clinic. The high anti-tumour activity of these novel binders has been related to a potent induction of cell death (apoptosis) and growth arrest selectively on the tumour cells expressing ErbB2. Importantly, due to the absence of any cytotoxic additives or moieties, these DARPin variants are expected to be devoid of adverse side effects. This property may translate into high therapeutic benefit in the clinical treatment. Finally, we conducted initial studies in animal models aimed at determining the cytotoxicity, biodistribution and pharmacokinetics of DARPins. The DARPins appeared to be well tolerated and localized to the tumour sites with very high specificities. We are therefore confident that DARPins can be used as effective vehicles for the ErbB2- mediated tumour targeting. Based on their high tumouricidal activity, specificity of targeting and low-cost production, they can be potentially envisaged as candidates to complement or even substitute antibodies in a number of therapeutic applications. Prof. Dr. Andreas Plückthun Biochemisches Institut Universität Zürich Winterthurerstrasse 190 8057 Zürich Phone +41 (0)44 635 55 70 Fax +41 (0)44 635 57 12 plueckthun@bioc.uzh.ch 81

82 Pruschy Martin Microtubule interference as target for combined cancer therapy with ionizing radiation (OCS 02129-08-2007) Interference with microtubule function is a promising approach for anti-cancer therapy that has been extensively validated by the use of taxanes for the treatment of a wide variety of human malignancies. However, treatment with taxanes is limited by taxane-related toxicities and the development of multidrug resistance. This has prompted an ongoing worldwide search for novel microtubule-targeting agents (MSA), e. g. epothilones. We recently demonstrated that epothilones also offer a significant therapeutic potential in combination with ionizing radiation (IR). Thus this potent, combined treatment modality represents a promising strategy for efficacy-enhancement of tumour-directed radiotherapy and systemic but tumouroriented and rationally designed anticancer agents. Treatment with MSAs alone or in combination with IR directly targets tumour cells, but it also affects other critical structures of the tumour, e. g. the tumour vasculature, which co-determines the tumour treatment response. However, these processes and the signalling consequences relevant for their cytotoxic effect are far from clear. In this research project we investigated in a multilayered approach the mechanisms underlying the antitumour effects of microtubule interference with epothilones alone and in combination with IR. In multiple tumour cell lines (lung and colon adenocarcinoma cell lines, fibrosarcoma, glioblastoma and medulloblastoma) and in murine tumour models derived from these cells, the efficacy of epothilones and IR alone and in combination was determined. Having access to a genetically-defined tumour cell system (wild-type lung adenocarcinoma cell line A549 and the mutant A549EpoB40 cell line, which are resistant to epothilones due to a -tubulin mutation) we could perform complementary in vitro and in vivo experiments specifically investigating the role of the tumour microenvironment to this combined treatment modality. We could demonstrate that the major cytotoxic effect of the combined treatment modality of IR and patupilone is directed against the tumour cell compartment and that the induced anti-angiogenic effect, which contributes to the supra-additive treatment response of this combined treatment modality, derives indirectly from the tumour cell. At the same time, we demonstrated that the potency of patupilone alone is independent of tumour hypoxia. Besides classic additive cytotoxicity determined on the single cell level, we identified that microtubule interference counteracts radiation-induced stress responses and thereby downregulates treatment thresholds. In particular, we determined interference on the level of VEGF secretion and matrix metalloproteinase activity and demonstrated that regulation of these paracrine effects contributes to the supra-additive treatment response of this combined treatment modality on the in vivo level. Besides these mechanistic insights, these new data in combination with our previous studies have already contributed to the design and launch of clinical trials with this combined treatment modality at the international level. Furthermore, and based on our data, we are currently outlining several options to combine IR not only with epothilones but also with other microtubule de-/stabilizing agents for clinical trials. Prof. Dr. Martin Pruschy Labor für molekulare Radiobiologie Klinik für Radio-Onkologie UniversitätsSpital Zürich Rämistrasse 100 CH-8091 Zürich Phone +41 (0)44 255 85 49 martin.pruschy@usz.ch Radtke Freddy The role of Notch2 in murine epidermis (OCS 01560-08-2004) The skin epidermis and its appendages represent a constantly renewing physical barrier that protects against mechanical injuries, infective organisms and excessive loss of water. Cellular processes such as proliferation, migration and cell death must be highly regulated in order to ensure lifelong homeostasis. The Notch pathway plays a key role in differentiation of the epidermis and its appendages. Notch proteins comprise a family of four type I transmembrane receptors that influence cell fate decision and differentiation processes in multiple organisms and tissues. In the haematopoietic system, signalling via Notch1 or Notch2 is important for the generation of T cells and a certain subpopulation of B cells, both of which have an important function in the immune system. Moreover, aberrant Notch1 signalling in the haematopoietic system is oncogenic and causative of T cell leukaemia. Results from the blood system but also other tissues suggested that aberrant Notch signalling is mostly associated with oncogenic properties. However, evidence from our own laboratory and from others has shown that Notch1 can also function as a tumour suppressor in particular in the skin. Conditional inactivation of Notch1 in the mouse epidermis leads to the development of spontaneous basal cell carcinoma-like tumours within 1 year after loss of Notch1 function. The relatively long latency for skin tumour development suggests that during this period additional mutations have to be acquired to cause malignant growth of Notch1 deficient skin. The murine skin expresses mostly two Notch receptors, Notch1 and Notch2. The function of the second Notch receptor in the skin was completely unknown. We therefore generated mice in which Notch2 alone or both Notch1 and Notch2 could be inactivated simultaneously in the skin. Our study showed that inactivation of Notch2 in the skin did not lead to any apparent phenotype, because loss of Notch2 function was fully compensated by the presence

of Notch1. However, simultaneous inactivation of both Notch1 and Notch2 in the skin differed from skin specific Notch1 mutant mice. Simultaneous loss of both receptors in the skin induced the development of a severe form of atopic dermatitis (also known as eczema), which is associated with massive inflammation within 4 weeks. Likewise, analysis of patients with atopic dermatitis but no other skin diseases (such as psoriasis) showed also a marked reduction of Notch receptor expression in the skin. Loss of Notch in keratinocytes induces the production of thymic stromal lymphopoietin (TSLP), a cytokine deeply implicated in the pathogenesis of AD. The AD-like associated inflammation is accompanied by a lethal myeloproliferative disorder (MPD) characterized by an increase in immature myeloid populations in the bone marrow and spleen. Transplantation studies revealed that the MPD is cell nonautonomous and caused by dramatic microenvironmental alterations. Genetic studies demonstrated that the increased G-CSF concentration in the serum of the Notch mutant mice is responsible for the MPD. Our study demonstrates a critical role for both Notch receptors in repressing TSLP production in keratinocytes, thereby maintaining integrity of the skin and the haematopoietic system. Prof. Dr Freddy Radtke Institut suisse de recherche expérimentale sur le cancer (ISREC) Faculté des sciences de la vie EPF de Lausanne (EPFL) Station 19 CH-1015 Lausanne Phone +41 (0)21 693 07 71 freddy.radtke@epfl.ch Radtke Freddy The role of Notch1 signaling in acute lymphoblastic T cell leukaemia (T-ALL) (KLS 01840-02-2006) T cells are haematopoietic cells that are part of our immune system to protect us against foreign invaders. T cell development occurs in the thymus, where unspecified bone marrow progenitors differentiate and mature within a period of approximately three weeks into functional T cells. This differentiation process is regulated and driven by several ligand-receptor interactions that induce a complex transcriptional network that assures proper growth and differentiation of functional T cells. Deregulation of these processes, combined with the acquisition of genetic alterations, is causative of leukaemogenesis. T cell acute lymphoblastic leukaemia (T-ALL) is an aggressive malignancy that originates in the thymus. The disease represents 15 % of paediatric and 25 % of adult acute lymphoblastic leukaemia (ALL) cases. The general treatment consists of multi-agent chemotherapy, which results in an overall survival rate of 70 % for children and 30 40 % for adults. Although the cure rates appear to be relatively high, 30 % of children and 60 % of adult patients relapse and have a poor prognosis. It is therefore important to better understand the molecular mechanisms contributing to malignant T cell growth. The Notch1 receptor is part of a family of transmembrane bound receptors that mediate signals from the outside to the inside of a cell and thereby influence development and growth. Physiological Notch1 signalling in the blood system and in particular in the thymus is essential for generating T cells. However, too much signalling causes malignant growth. More than 50 % of all T-ALL patients have small changes within the receptor (called point mutations); this causes the receptor to signal too strong, too long and at inappropriate stages of development and thus causes leukaemia. We generated a Notch driven leukaemic mouse model that recapitulates the human disease and showed that Notch signalling is not only required for the development of the disease but continuous signalling is also essential for the maintenance of the disease. Thus Notch1 is a master regulator for malignant T cell growth. Further, we investigated the role of the transcription factor Hes1 for normal and malignant T cell growth and development. Hes1 is one of numerous transcription factors that become activated when Notch1 signals. Our studies showed that under physiological conditions Hes1 is important for normal T cell development. In its absence only very few T cells are able to develop. More importantly, we showed that Hes1 is essential for the development and maintenance of Notch1 driven leukaemia in our mouse model. Most importantly, reducing Hes1 protein levels in established patient-derived human T-ALL samples resulted in growth retardation and cell death, strongly suggesting that the important role for Hes1 might not be restricted to T-ALL mouse models but could also apply to the human disease. Thus, our studies identified Hes1 as a main mediator of Notch1 signalling in the physiological and leukaemic situation and highlight it as a potential therapeutic target to fight against malignant growth of T-ALL. Prof. Dr Freddy Radtke Institut suisse de recherche expérimentale sur le cancer (ISREC) Faculté des sciences de la vie EPF de Lausanne (EPFL) Station 19 CH-1015 Lausanne Phone +41 (0)21 693 07 71 freddy.radtke@epfl.ch 83

84 Renner Christoph Selective inhibition of intratumoral regulatory T cells by antibody-gitr ligand fusion proteins (OCS 02119-08-2007) Cancer patients possess tumour-reactive T cells, but these are suppressed by naturally occurring regulatory T cells (Treg cells). Activation or support of these tumour-reactive T cells is therefore a major objective in cancer immunotherapy. Stimulation of glucocorticoid-induced tumour necrosis factor-related receptor (GITR) represents a promising approach, since this receptor is expressed on both CD4 + and CD8 + effector T cells as well as on CD4 + 25 + Treg cells. Triggering of murine GITR with its natural ligand (GITRL) or anti-gitr agonistic antibodies enhances T cell responses, inhibits Treg mediated suppression and thereby induces tumour immunity in a variety of murine tumour models. However, systemic administration of costimulatory agents can lead to global T cell activation and autoimmunity. Therefore, we proposed to specifically manipulate the T cell compartment in the tumour microenvironment by using a bispecific fusion protein combining mgitrl and a single chain antibody that targets fibroblast activation protein (FAP). Accumulation of antifap-mgitrl in the tumour microenvironment can be mediated through binding to FAP, which is specifically expressed on sarcomas and on cancer-associated fibroblasts (CAFs) found in the stroma of epithelial cancers. The antifap-mgitrl fusion protein generated in this study formed dimers and bound to murine GITR with an affinity of 1.2 μm and to murine FAP with an affinity of 4.5 nm. In vitro cell assays with murine splenocytes showed that our antifap-mgitrl fusion protein can stimulate CD8 + and CD4 + effector T cells, as shown by their increased proliferation and production of IFN-g and IL-2. This costimulatory effect was enhanced when the fusion protein was presented by a FAP-positive cell line mimicking FAP + CAFs or FAP + tumours. Presumably, the membrane-bound antifap-mgitrl allows for cross-linking of multiple GITR molecules on T cells, thus leading to increased signalling and enhanced costimulation. In vitro, Treg cells inhibit the expansion and function of CD8 + T cells. Addition of our antifap-mgitrl to the Treg: CD8 + T cell coculture could restore proliferation and IFN-g production of CD8 + T cells. Furthermore, cell membranebound antifap-mgitrl was 100-fold more effective in overcoming Treg-mediated suppression compared to unbound fusion protein. To translate the in vitro results in a preclinical model, we established syngeneic murine cancer models to either target the tumour stroma or the tumour cells directly. Immunotherapeutic antifap-mgitrl treatment of a colon carcinoma provoked no delay in tumour growth due to weak stroma formation. However, therapy of a FAP + osteosarcoma led to enhanced survival of mice treated with anti FAP-mGITRL. The antibody-directed delivery of GITRL opens a new path to positively act on the local T cell environment in the tumour. Targeted delivery and thereby enhanced immunomodulatory effects of antifap-mgitrl represent a promising approach in antibody-based tumour immunotherapy. Prof. Dr. Christoph Renner Klinik und Poliklinik für Onkologie Medizinbereich Innere Medizin Onkologie UniversitätsSpital Zürich Rämistrasse 100 CH-8091 Zurich Phone +41 (0)44 255 21 54 christoph.renner@usz.ch Romero Pedro Impact of lentiviral cancer vaccines on the anti-tumour response in vivo (OCS 2011-02-2007) The incidence of malignant melanoma continues to increase in our country in people of all ages. Except for early detection and surgical excision, the currently available treatments fail to cure this disease. Thus, new effective therapies for metastatic melanoma are urgently needed. The development of cancer vaccines is a promising approach, and recent results in this field are encouraging. To optimize them, it is necessary not only to enhance their ability to induce specific immunity but also to prove their ability to control or even reject established tumours. We have recently reported the development of recombinant lentivectors carrying tumour specific antigens as vaccines. Results with lentiviral immunization in mice demonstrate their ability to induce strong and long-lived specific T cell responses, even with a single injection. Typically, the peak of specific T cell responses is attained during the third week post immunization, and stable levels of immune memory can be detected as long as six months later. Importantly, this response is sufficient to protect from melanoma tumour challenge, even when this is performed six months after a single immunization. However, the key quality expected from vaccination against cancer is its ability to control established large tumours rather than to confer a prophylactic protection. In this regard, we observed that the therapeutic vaccination failed to exert any detectable control of tumour growth. A detailed analysis of this vaccine failure revealed that while effector CD8 T cells are able to home to the tumour sites, they are compromised in their ability to function normally. Indeed, vaccine induced T cells are inactivated by many immunosuppressive factors active in the tumour microenvironment. We identified the selective overexpression on specific T cells of the inhibitory receptor PD-1 as one of the pathways leading to T cell dysfunction. We therefore tested combination therapies, whereby vaccination was either preceded by chemotherapy (single injection of cyclophosphamide) or followed by administration of antibodies blocking both PD-1 and its main ligand PD-L1. In both cases we clearly observed a stronger effect on retardation of tumour growth and increase of mouse survival. These results indicate that the combination therapies can synergize in affording protection.

Together, the results of this project demonstrate the promise of this lentiviral based vaccine. They also clearly illustrate the need for combining effective vaccines with immunomodulatory compounds that can leverage tumour protection by relieving the immunosuppressive tumour environment. Similar conclusions have been reached by independent laboratories using a relatively large variety of anti-cancer vaccines. Thus, translation of these results to the clinic calls for efforts to identify the best combination therapies in terms of clinical efficacy. We plan to continue our preclinical studies with the aim of accelerating the process of identification of effective combinatorial immunotherapies. Prof. Dr Pedro Romero Division d onco-immunologie clinique Centre Ludwig de recherche sur le cancer Avenue Pierre-Decker 4 CH-1005 Lausanne Phone +41 (0)21 314 01 98 Fax +41 (0)21 314 74 77 pedro.romero@inst.hospvd.ch Rüegg Curzio Role of integrins and CYR61/CCN1 in tumor metastasis: Unraveling mechanisms and development of novel integrin inhibitors (OCS 02020-02-2007) Introduction Tumour progression to local invasion and metastasis formation are of utmost clinical relevance, since they often determine patient prognosis. Furthermore, cancers relapsing after initial therapy tend to become more aggressive, are more difficult to treat and form metastases more often. Despite the clinical relevance, however, the cellular and molecular mechanisms governing the formation of metastases are still not well understood. Thus, there is a profound need to develop new therapeutic tools capable of interfering with metastasis formation. We recently identified the extracellular matrix (CYR61/CCN1) and one of its receptors (integrin avb5) as two proteins collaborating to promote metastasis of cancers relapsing after radiotherapy. Importantly, a pharmacological inhibitor of the receptor prevented metastasis formation. But the exact mechanisms beyond this effect are not well known.

86 Goal Here we build on these observations to characterize the cellular and molecular mechanism by which these two proteins cooperate to promote invasion and metastasis. The goal is then to interfere with their function as a novel therapeutic strategy to prevent metastasis. Specifically, we are studying the effects of CYR61/CCN1 on cancer cell adhesion, invasion and metastasis by analyzing events in the cancer cell and by studying how these proteins favour cancer cell interactions with tumour vessels, the first step toward metastasis. In addition, we will develop novel small molecular inhibitors of the receptor based on computer-assisted molecular modelling. Methods We use combined molecular biology, genomic, cell biology and biochemical experiments to address the research questions. These experiments will be largely performed in vitro without the need of mice. Computer-assisted molecular modelling will benefit from recent technical advances at the Swiss Institute of Bioinformatics. Results We generated different normal and breast cancer cell lines expressing high level of CYR61 and observed that these cells become more invasive through a process called epithelial-to-mesenchymal transition. We also identified cellular signalling pathways associated with this effect. Their pharmacological targeting prevented epithelial-to-mesenchymal transition. These results demonstrated for the first time that CYR61 induces epithelial-to-mesenchymal transition. In the second part of the project we developed a model of the receptor integrin a5b1 obtained by modelling the experimental structures of homologous receptors as templates. The model can reproduce the correct ligand binding mode for a natural ligand. We then used this model to design structurally diverse ligands, which will be applied to generate novel inhibitors to test in competition assays. Benefits for patients Results obtained from these experiments are of broad relevance to both tumour biology and clinical oncology. For one, they aid understanding of some aspects of the mechanisms leading to metastasis, and for another, they may open up new therapeutic perspectives to prevent or treat metastases. Inhibitors of integrins are currently in advanced clinical trials in brain cancer, with promising results. We are now considering designing a clinical trial to test the safety and activity of integrin inhibitors in preventing metastasis in patients experiencing relapses after radiotherapy. Prof. Dr Curzio Rüegg Division de pathologie expérimentale Université de Fribourg 1, rue Albert-Gockel CH-1700 Fribourg Phone +41 (0)26 300 87 66 Fax +41 (0)26 300 97 33 curzio.ruegg@unifr.ch Rufer Nathalie Defining molecular, structural and functional T-cell receptor properties of melanomaspecific human CD8 + T lymphocytes (OCS-1995-02-2007) Although tumour-reactive T lymphocytes can be detected in cancer patients, these immune responses often fail to control or eliminate the disease. It has been proposed that T cells directed against tumour antigens express T-cell receptors (TCR) of lower affinity/avidity for their antigenic ligands than pathogen-specific T lymphocytes. Today, recent progress unveiling the cellular and molecular basis of the immune response allows the design of novel strategies for tumour immunotherapy. Adoptive transfer of T cells engineered with TCRs has been recently developed with the aim to induce immune reactivity towards defined tumour-associated antigens to which the endogenous T-cell repertoire is non-responsive. An attractive approach to improve this strategy is to optimize the TCR sequence to increase its affinity for cognate tumour antigen. Olivier Michielin s group (at the Swiss Institute of Bioinformatics in Lausanne) recently developed and applied a novel in silico structure-based approach for rational design of sequence mutations that preserve precise antigenic specificity while increasing the affinity to the peptide-mhc complex. The objectives of our study were: 1) to assess rigorously the impact of each optimized TCR variant on T cell function; and 2) to evaluate the potential usage of these TCRs for therapeutic interventions by adoptive T cell therapy. We generated a panel of T lymphocytes expressing tumour-specific TCR variants of incremental affinities. Essentially, TCR variants of increased affinity revealed enhanced T cell responses, in terms of cytokine secretion and target cell killing, correlating with upregulation of genes typically involved in T cell activation. Importantly, our results also allowed us, for the first time, to describe that optimal T cell function is limited to a given window of TCR-pMHC binding affinity, with a drastic reduction in cell responsiveness of T cells expressing either lower or higher TCR affinities. In conclusion, we recently established novel experimental strategies, allowing us to generate tumour-specific T lymphocytes expressing sequence-optimized TCRs. Thanks to this unique model we showed that T cell immune responses against cancer cells can be specifically and drastically improved. However, our study also revealed the presence of an affinity window for optimal T cell function. We are currently characterizing some of the parameters involved in regulation of TCR function. We propose that the rational optimization of TCR-pMHC binding above a given affinity window not only has the potential to cause cross-reactivity but also can result in drastic reduction of optimal effector function towards cancer cells. These results are of particular relevance for the treatment of patients with cancer by adoptive transfer of T cells genetically engineered to display affinity-optimized TCRs, as

they highlight the importance of assessing TCR avidity and efficacy for improved therapy. Identifying rationally optimized TCRs and expressing such tumour-specific receptors in T lymphocytes represents one of the most promising approaches to improving adoptive T cell therapy against cancer. Dr Nathalie Rufer Centre Ludwig de recherche sur le cancer Université de Lausanne c/o CHUV, HO 05/1532 Avenue Pierre-Decker 4 CH-1011 Lausanne Phone +41 (0)21 314 01 99 nathalie.rufer@unil.ch Ruiz i Altaba Ariel Determination of the extent of participation of the sonic hedgehog-gli signaling pathway in human gliomas and in their cancer stem cells (OCS 01857-02-2006) Human gliomas are devastating brain tumours (~2 % of total cancers in Switzerland) that are extremely difficult to treat. Most of these tumours are resistant to the usual chemotherapeutical agents and to radiotherapy. Moreover, because they often spread to adjacent tissues, glioma tumours are almost impossible to remove by surgery and are therefore associated with a high mortality rate (within 12 months). Even if it is known that gliomas develop from cancerous glial cells, the molecular mechanisms involved in this process are poorly understood. Recently, we and others found that the sonic hedgehog (SHH)-GLI signalling pathway, a pathway known to participate in embryonic development, is required for the growth and the survival of many different type of tumours, including gliomas. Moreover, we and others showed previously that SHH- GLI also regulates the behaviour of normal stem cells during brain development in the mouse. All together, these results prompt us to understand how the SHH-GLI signalling pathway regulates the behaviour of glioma tumours and their cancer stem cells. To this purpose, we will analyse the growth and the survival of primary tumourigenic cells coming from patient biopsies and xenografted in mice. In parallel, we propose to study the properties of regeneration, differentiation and generation of tumours of the cancer stem cells present in gliomas. The advances in the understanding of the molecular mechanisms sustaining the biology of gliomas and their cancer stem cells produced by this study should be an aid to devising and developing new efficient therapies against this destructive cancer. Prof. Dr Ariel Ruiz i Altaba Département de génétique médicale et de développement Faculté de médecine Université de Genève 1, rue Michel-Servet CH-1211 Genève 4 Phone +41 (0)22 379 54 46 Fax +41 (0)22 379 59 62 ariel.ruizaltaba@unige.ch Schär Primo Clarification of newly emerging roles of DNA repair in mediating the cytotoxicity of 5-fluorouracil and in the maintenance of epigenetic stability (OCS 01868-02-2006) Background of the study Every day, damage occurs to DNA bases in our cells thousands of times, mostly in the form of small chemical modifications that are either cytotoxic or mutagenic. To avoid genetic mutation, cells need to repair the DNA damage. In this process, DNA glycosylases first recognize and excise the base lesions. TDG (thymine DNA glycosylase) is one of these enzymes, and its ability to remove uracil (U) and thymine (T) from DNA when mispaired with guanine (G) implicates a function in avoidance of genetic mutations from deaminated cytosine and 5-methylcytosine bases in DNA. The failure of repair would generate C T mutations that often contribute critically to carcinogenesis. However, TDG also detects and processes 5-fluorouracil (5-FU) in DNA. 5-FU is a uracil analogue commonly used as a chemotherapeutic drug against cancer. Exposure of cells to 5-FU favours misincorporation of uracil and 5-FU into genomic DNA. The processing of these bases by DNA repair activities was proposed to account for the DNA-directed cytotoxicity of the drug, but underlying mechanisms have not been resolved. Aim The aim of this study was to clarify the contribution of TDG-dependent base excision to the response of cells and cancers to 5-FU, and to the suppression of carcinogenesis through the maintenance of genetic and epigenetic stability. Methods and approach We generated mouse cell lines with targeted disruptions of the Tdg gene. Matched TDG deficient and proficient cell lines were then used to assay the impact of 5-FU treatment on cell survival, cell cycle progression and the generation of drug-induced DNA damage. To address the role of TDG in tumour suppression and as a basis for follow-up studies, we started to profile TDG expression in human cancers. Findings of the study The following summarizes the results finalizing the first part of the study. These were published in PLoS Biology and establish a role for TDG in the cellular response to 5-FU. Genetic inactivation of TDG significantly increased cellular resistance towards 5-FU. We found that excision of DNA-incorporated 5-FU by TDG generates persistent DNA strand breaks, delays DNA duplication and activates cellular DNA damage signalling. In the absence of TDG, however, repair of 5-FU induced DNA strand breaks is more efficient. We thus concluded that excision of 5-FU 87

88 Method and Approach We employed embryonic stem (ES) cells as an in vitro model. We differentiated them into neuronal progenitors and terminal neurons and furthermore compared them to embryonic carcinoma (EC) cells. Using the MeDIP technique to measure DNA methylation and chromatin immunoprecipitation technique to measure histone modificaby TDG prevents efficient downstream processing of repair intermediates, thereby mediating DNA-directed cytotoxicity. The status of TDG expression in a cancer is therefore likely to determine its response to 5-FU-based chemotherapy. Prof. Dr. Primo Schär Institut für Biochemie und Genetik Departement Biomedizin Universität Basel Mattenstrasse 28 CH-4058 Basel Phone +41 (0)61 267 07 67 Fax +41 (0)61 267 35 66 primo.schaer@unibas.ch Schär Primo The role of thymine DNA glycosylase in the maintenance of genetic and epigenetic stability and the suppression of tumorigenesis (OCS 2193-02-2008) Background of the study To maintain the integrity of genetic information, every cell of your body uses repair systems to remove damage occurring to DNA. The most prevalent DNA lesions are small chemical modifications of the DNA bases, and these are recognized and removed from DNA by specialized enzymes. TDG belongs to this class of enzymes. It removes uracil (U) and thymine (T) when mispaired with guanine (G). Such mispairs in DNA arise frequently by spontaneous deamination of cytosine or 5-methylcytosine, respectively. In addition to the repair of these lesions, TDG has been implicated in the regulation of gene transcription and in the control of cytosine methylation. Cytosine methylation in DNA serves as a molecular tag to activate or inactivate genes. In cancerous cells these tags are often inaccurately set, thereby avoiding the expression of genes that act against tumour development. Although its biological function remains to be clarified, the available evidence strongly suggests that TDG act against genetic mutation and stabilizes gene expression, both of which are important tumour suppressor functions. Thus, TDG is likely to play a critical role in tumour suppression. This study was designed to address the putative tumour suppressor function for the first time directly in human cancers. Aims The aims of this study were to analyze the expression status of TDG in different human cancers and the respective normal tissue, to identify molecular causes of the potential loss of TDG expression in cancer cells and to characterize epigenetic and genetic instabilities in such cancers. Methods and approach We developed immunohistochemical methods for specific staining of TDG in tissue sections. These methods were used to compare presence and levels of TDG protein in various human cancers with those in the respective nor mal tissues. In addition, we established methods allowing the analysis of cytosine methylation in gene regulatory regions and used these to assess the effect of TDG expression on the status of cytosine methylation. Findings of the study The systematic analysis of TDG expression in normal and cancerous tissues generated interesting results. In most normal tissues, TDG was inhomogenously expressed and present only in a subset of cells. The mean number of TDG expressing cells varied in a tissue-dependent manner, ranging from less than 10 % (breast) to over 80 % (brain). In tumours, however, such patterns of TDG expression were dramatically changed, most prominently in the colorectal cancers. In comparison to normal colorectal epithelium, which showed about 30 % TDG positive cells, the amount of TDG expressing cells in the cancer tissue was reduced to an average of 4 %. Strikingly, most colorectal tumours presented with a complete absence of TDG protein. Initial molecular analysis of these tumours revealed an increase of cytosine methylation in the regulatory regions of the Tdg gene and of other genes. Altogether, our data suggest that the absence of TDG brings about instability in gene expression, conferring a selective advantage to cancer forming cells. Prof. Dr. Primo Schär Institut für Biochemie und Genetik Departement Biomedizin Universität Basel Mattenstrasse 28 CH-4058 Basel Phone +41 (0)61 267 07 67 Fax +41 (0)61 267 35 66 primo.schaer@unibas.ch Schübeler Dirk Role and plasticity of DNA methylation in stem cell pluripotency and cancer (KLS 01865-02-2006) In recent years, stem cells have been discovered in many adult tissues throughout the body, where they differentiate into specific cell types and help to regenerate the tissue. In addition, scientific studies suggest that these adult stem cells can transform into cancer stem cells. Next to genetic mutations, epigenetics changes might play a role in this aberration. In this study we determined the dynamics of DNA methylation, an epigenetic modification, during normal differentiation and explored its potential to differentiate between normal and cancer stem cells. Aim The goal of the study was to identify epigenetic markers of cancer stem cells, i.e. genomic regions that are specifically DNA methylated or unmethylated in cancer stem cells.

tions in conjunction with microarrays, we determined the epigenetic state of 26,500 genes in each cell type and compared this with the respective expression patterns. A bioinformatics analysis system was developed to compare the different measurements in the different cell types. Results of study The DNA methylation profiles of the EC and ES cells showed only subtle differences, indicating that changes in DNA methylation might not be an early feature of promoters in the transition from ES to EC cells. Histone modification profiles were subsequently created and showed greater plasticity. The chromatin state of the promoters studied was also compared with the expression states of the respective genes. A study of the differentiation of ES cells into neurons revealed context-dependant cross-talk between Polycomb-mediated histone methylation and DNA methylation, leading us to the idea that Polycomb targets might become methylated at a later stage in cancer stem cell development. Promoters becoming methylated in the differentiation to neurons are enriched for pluripotency genes, which are unmethylated in both the ES and the EC cell lines studied. Dr. Dirk Schübeler Friedrich Miescher Institut für biomedizinische Forschung (FMI) Maulbeerstrasse 66 CH-4058 Basel Phone +41 (0)61 697 82 69 Fax +41 (0)61 697 39 76 dirk@fmi.ch Schwaller Jürg PIM serine/threonine kinases as potential therapeutic targets in human haematological malignancies (OCS 01830-02-2006) Malignant disorders of the haematopoietic system are often associated with uncontrolled activity of proteins with enzymatic activity of protein kinases. These kinases transfer phosphate molecules on their substrates (on serine, threonine or tyrosine residues) and hereby deliver a wide variety of cellular signals. We showed previously that most cases of acute and chronic leukaemias are associated with overexpression of the constitutively active PIM serine/threonine kinases (PIM1, PIM2) that are essential for uncontrolled growth and survival of leukaemic cell lines and primary blasts. The goals of this project were: 1) to characterize novel small molecule PIM inhibitors; and 2) to better understand the molecular mechanisms underlying the leukaemogenic activity of PIM kinases. Working in close collaboration with structural chemists, we were able to identify several small molecules that selectively interacted and blocked PIM kinases. These PIM kinase inhibitors also significantly reduced growth and survival of leukaemic cell lines and primary blasts from patients. We studied the role of PIM kinases in induction and maintenance of the disease in a mouse leukaemia model. Our experiments revealed that PIM1 (but not PIM2) has a so far unknown function in regulation of cellular migration to the bone marrow. PIM1 seems to functionally regulate the CXCL12/CXCR4 chemokine ligand/receptor signal trans duction pathway. After binding the ligand, the CXCL12/ CXCR4 ligand/receptor complex gets internalized and activates multiple signals that control cellular adhesion and migration. A part of the molecules becomes degraded and newly formed, but the majority of the receptor is recycled to the cell surface. We were able to show that PIM1 phosphorylates a distinct amino acid residue (serine 339) located in the intracellular tail of the CXCR4 receptor. Cells lacking PIM1 show reduced recycling to the cell surface, resulting in lower numbers of CXCR4 receptor molecules at the surface, which is associated with reduced homing and migration of haematopoietic stem cells to the bone marrow. Leukaemic cells (cell lines or primary blasts) with elevated PIM1 levels exhibit more CXCR4 molecules on the surface and enhanced cellular adhesion and migration. Interestingly, treatment of the cells with our novel PIM inhibitors significantly reduced the number of surface CXCR4 molecules and migration of leukaemic cells. Our work not only revealed a previously unknown molecular mechanism underlying the leukaemogenic activity of PIM kinases but also opened up the possibility to modulate adhesion and migration of normal and leukaemic haematopoietic stem cells with small molecule PIM kinase inhibitors. These observations have provided additional rationale for PIM kinase inhibitors to enter first clinical trials. Prof. Dr. Jürg Schwaller Forschungsgruppe Kinderleukämie Departement Biomedizin Universitätsspital Basel Hebelstrasse 20 CH-4031 Basel Phone +41 (0)61 265 35 04 Fax +41 (0)61 265 23 50 j.schwaller@unibas.ch Skoda Radek C. Pathogenesis of myeloproliferative disorders (OCS 01742-08-2005) Myeloproliferative disorders (MPD) are chronic blood diseases characterized by overproduction of blood cell precursors in the bone marrow. Patients with MPD bear an increased risk (5 20 %) to develop an acute leukaemia after a variable latency. Therefore, MPD is often considered a pre-leukaemia. We found that in about 70 80 % of MPD patients, the blood stem cells carry a mutation in the gene Janus kinase 2 (JAK2). JAK2 is an enzyme that transmits signals coming from the outside into the cell and the mutation (JAK2-V617) amplifies the growth-promoting effect of these signals, so that more blood cells are formed. The aim of our studies is to better understand how the JAK2-V617F mutation causes MPD, with which partner genes it collaborates in this process and what the predisposing events are that can favour the acquisition of MPD. 89

90 To address these questions, we are combining detailed analysis of cells and tissues from patients with MPD with mouse models of MPD. Our studies in patients revealed that JAK2-V617F may be preceded by as yet unknown mutations. To follow up on this observation, we studied patients with MPD that in addition to JAK2-V617F have deletions of chromosome 20q (del20q) or carry mutations in a gene called TET2, and we determined the temporal order in which these mutations were acquired. Our studies showed that there is no fixed order of events, and some patients acquire JAK2-V617F first, followed by del20q or TET2 mutations, whereas in other patients with MPD the inverse order can be observed. Thus, deletions of chromosome 20 and mutations in TET2 are unlikely to represent pre-disposing events for JAK2-V617F, and we are examining other candidate genes for such a function in familial forms of MPD. A second question that we are addressing is why the JAK2-V617F mutation can cause 3 different subtypes of MPD, namely, essential thrombocythemia (ET) with elevated platelet levels, polycythemia vera (PV) with increased numbers of red cells and in some cases primary myelofibrosis (PMF) with fibrosis of the bone marrow and blood formation in the spleen and liver. We generated a mouse model of MPD that expresses the mutant JAK2- V617F and displays all 3 types of MPD. We found that ET develops when the mutant human JAK2-V617F is expressed at lower levels, while at higher levels PV phenotype can be observed. Myelofibrosis occurred later in these mice and appears to correlate with the platelet counts. Interestingly, when we made a mutation in a different position in JAK2 that is associated with a pure red cell phenotype in patients (JAK2 exon 12 mutation), we observed a pure red cell elevation in the mice, i.e. the same phenotype as in patients. Thus, in addition to expression levels, the different JAK2 mutations may also cause different quality of signals that favour the expansion of specific blood cell types. Finally, inhibitors have been developed that can reduce the enzymatic activity of JAK2 and are undergoing clinical trials in patients with MPD. Our mouse models have proven to be valuable in testing such compounds. Our projects on JAK2 have contributed to changing the diagnostic and therapeutic approach to patients with MPD. We are now examining how other known gene mutations collaborate with JAK2 mutations and are searching for as yet unknown new gene mutations in MPD. Prof. Dr. Radek C. Skoda Forschungsgruppe experimentelle Hämatologie Departement Biomedizin Universitätsspital Basel Hebelstrasse 20 4031 Basel Phone +41 (0)61 265 22 72 Fax +41 (0)61 265 32 72 radek.skoda@unibas.ch Suter Beat Control of the cell cycle function of Xpd and Cdk7 (OCS 01834-02-2006) The Xpd gene aids our body in different ways to prevent cells from turning into tumour cells. Many patients with a genetic defect in the Xpd gene have a one to two thousand-fold increase in cancer risk. Whereas skin cancer is the most prevalent form, other tissues can be affected as well. It was known for some time that one of the functions of this XPD is to repair the genetic material once it gets damaged in certain ways. However, it was also known that the reduced repair capacity alone does not necessarily lead to this very high cancer incidence in patients. We tried to elucidate novel functions of Xpd, and we wanted to find out whether these functions could play important roles in preventing tumour formation. To be able to identify additional novel functions of XPD and to analyze them, we developed a model system in which the previously known activities of XPD are not required. We were able to develop such a model in an intact organism by using the embryo of the fruit fly Drosophila. Using this model we found that the XPD protein is a truly multifunctional protein that helps to organize the division of cells and that coordinates this process with other cellular processes. If it fails to function properly, the genetic material is not distributed equally to the ensuing daughter cells. As a consequence, daughter cells arise that lack pieces of chromosomes or even entire chromosomes. This instability of the genome is a decisive step in tumour formation. Identifying the need for XPD to prevent this instability in our model system was a big step forward in finding out the causes of this devastating disease. The diverse functions of XPD make it a truly fascinating multifunctional protein. It performs diverse cellular functions and acts through several different cellular processes. The cells need to tightly coordinate these diverse processes for the body to function properly. In the course of our experimental work we realized that XPD is able to coordinate these processes by acting as a dispatcher for another protein complex named CAK. XPD sends CAK at the correct time to the appropriate place in the cell, where it can act on the local target substrates. At the same time, the localization to a new region terminates CAK activity towards a previous target that should no longer be activated at this point. Therefore, by sending CAK to the right place at the right time, the dispatcher controls and coordinates these different cellular processes. As described at the beginning, malfunctioning of this XPD in human patients can lead to highly elevated cancer risk in Xpd patients. Combining our own studies with earlier studies we came to the conclusion that the very strongly elevated cancer risk arises most likely in Xpd patients in which the failure to repair the genetic material combines with defective Xpd activity in organizing and controlling the cell division. It seems likely that as long as one of the two functions is still active, the cancer risk is only moder

ately elevated. In summary, Xpd protects our genetic material in different ways, and it therefore acts as a veritable bodyguard to our genetic material. Prof. Dr. Beat Suter Institut für Zellbiologie Universität Bern Baltzerstrasse 4 CH-3012 Bern Phone: +41 (0)31 631 47 15 beat.suter@izb.unibe.ch Tschan Mario P. Regulation of the DMP1-ARF-p53 tumor suppressor pathway in normal and leukemic hematopoiesis (OCS 01823-02-2006) Cyclin D binding myb-like protein 1 (DMP1) is a haploinsufficient tumour suppressor involved in positively modulating the alternative reading frame (ARF)-p53 signalling pathway. This pathway is inactivated in most cancers, including leukaemias, and further understanding of its regulation might provide novel options for cancer treatment. DMP1 is a direct transcriptional activator of ARF and of CD13, a gene involved in myeloid differentiation. Using lentiviral vectors to express shrna for gene knockdowns or transgenes as well as promoter reporter and proliferation assays, we identified novel transcriptional, posttranscriptional and posttranslational regulators of the DMP1 tumour suppressor. Moreover, we showed that a dominant negative splice variant of DMP1, DMP1 beta has oncogenic properties by inhibiting the full-length DMP1 and promoting cellular proliferation. In addition, we found aberrant expression of this splice variant in acute myeloid leukaemia patients samples as compared to healthy controls. In summary, we discovered a variety of novel mechanisms to inactivate the DMP1 tumour suppressor in myeloid leukaemias, or other tumours, and propose the following DMP1 repression models: 1) enhanced expression of the dominant negative DMP1 beta splice variant leading to reduced ARF levels and thus aberrant proliferation; 2) altered expression of micrornas, which target DMP1; and 3) inactivation of positive DMP1 regulators, such as the transcription factor OCT1 and or the kinase DAPK2. Dr. Mario P. Tschan Medizinische Onkologie/Hämatologie Departement für klinische Forschung Universität Bern MEM E829 Murtenstrasse 35 CH-3010 Bern Phone +41 (0)31 632 87 80 mtschan@dkf.unibe.ch Walker Paul R. Exploration of intracerebral immune responses in a spontaneous astrocytoma model and their exploitation in novel cancer therapies (OCS 1754-08-2005) In this study we used a transgenic mouse model in which brain tumours spontaneously arise to understand the interactions of the immune system with the developing cancer. This is difficult to study in patients, because the limited tumour samples that are available for analysis are generally from advanced cancers, or after treatment. We studied mice before they developed any cancer related symptoms, and also when they became ill. We isolated immune cells from lymph nodes and spleen, as well as from the brain, to assess the leukocyte subsets present and their functions. We then tested a vaccination approach to improve the potential anti-tumour immune response. Objectives Immunotherapy for patients with malignant gliomas may be a useful future treatment option. However, it is not clear whether this should aim to reinforce or re-program a pre-existing immune response. By analyzing the spontaneous gliomas that arise in the brains of GFAP-V 12 HA-ras transgenic mice, we aimed to determine whether brain tumours were detected by the immune system at an early stage, and whether anti-tumour immunity was functional at any stage, or could be induced or restored by vaccination. Methods In the GFAP-V 12 HA-ras model, mice spontaneously form astrocytomas that develop progressively and gradually increase in malignancy. We sacrificed individual mice at fixed time points while they were still healthy (4, 8, and 12 weeks of age) and also once they became terminally ill. Immune cells were isolated from dissociated brain and lymphoid tissues and were stained with antibodies to identify all principle leucocyte subsets. We stained for cytokines and cytotoxic molecules important for antitumour activity. Analysis was principally by flow cytometry. To augment the number of immune cells infiltrating the brain we used a vaccine comprised of a recombinant virus to induce immunity to brain tumour cells. Results There was an immune response induced by the tumour at early, non-malignant stages of glioma development, before the mice developed symptoms. However, the immune cells that first infiltrated the brain included many regulatory T cells that are capable of suppressing cytotoxic T cells that could otherwise attack the glioma. Consistent with this, the CD8 T cells that co-infiltrated the brain had low or absent expression of the cytotoxic molecule granzyme B and cytokines useful in anti-tumour immunity (interferon-g, TNF and IL-2). Peripheral vaccination with recombinant virus could augment interferon- expression by CD8 T cells, but only direct intracranial stimulation could restore granzyme B expression. 91

92 Translational relevance The results suggest that immunotherapy for glioma may be partially successful with peripheral approaches such as vaccination, but locally applied treatments or reducing immunosuppressive factors may be necessary for full efficacy. PD Dr Paul R. Walker Laboratoire d immunologie des tumeurs Centre d oncologie Hôpitaux universitaires de Genève (HUG) 4, rue Gabrielle-Perret-Gentil CH-1211 Genève 14 Phone +41 (0)22 372 98 80 paul.walker@hcuge.ch Wymann Matthias P. Phosphoinositide 3-kinases in melanoma (OCS 01924-08-2006) Advanced metastatic melanoma is refractory to conventional chemotherapy. Phosphoinositide 3-kinases (PI3Ks) are lipid kinases enzymes phosphorylating lipids at the plasma membrane and act as a key relay of growth, proliferation and cell migration. Initial studies using potent, broad-band PI3K inhibitors have demonstrated the sensitivity of melanoma to PI3K inhibition. Work with genetically targeted mice shows that broadband PI3K inhibitors affect metabolic control, the immune system and cardiovascular parameters. To minimize side effects, the role of specific PI3K isoforms on tumour autonomous control in melanoma will be investigated. In this context, a murine B16 cell tumour transfer model will be used. Altogether, the proposed work will define the prospect and the profile of future therapies targeting PI3Ks in melanoma. Prof. Dr. Matthias P. Wymann Institut für Biochemie und Genetik Departement Biomedizin Universität Basel Mattenstrasse 28 CH-4058 Basel Phone +41 (0)61 695 30 46 matthias.wymann@unibas.ch Further completed research projects from July 2008 to December 2010 Pelkmans Lucas OCS 02111-08-2007 CHF 198,000. Institut für molekulare Systembiologie, ETH Zürich, Zürich How focal adhesion kinase (FAK) controls membrane partitioning and endocytosis of cell adhesion components in normal and in cancer cells Stamenkovic Ivan OCS 01656-02-2005 CHF 173,900. Institut universitaire de pathologie de Lausanne (IUP), Centre hospitalier universitaire vaudois (CHUV), Lausanne Analysis of the molecular mechanisms underlying the pathogenesis of EWING S family tumors

Basic biomedical research List of approved research projects in 2009/2010 Total funds allocated: CHF 11,792,000. Aguet Michel KFS 02674-08-2010 CHF 234,400. Institut suisse de recherche expérimentale sur le cancer (ISREC), Faculté des sciences de la vie, EPF de Lausanne, Lausanne Role of BCL9/BCL9L in regulating Wnt-mediated epithelial-mesenchymal transition, stem cell traits and drug sensitivity in Wnt-activated human cancers Basler Konrad KFS 02443-08-2009 CHF 169,400. Institut für molekulare Biologie, Universität Zürich, Zürich Characterization of the role of histone binding by the WnT-signalling components Pygo2 in murine models of breast cancer and colon cancer 93 Becher Burkhard KFS 02441-08-2009 CHF 203,000. Institut für experimentelle Immunologie, Departement Pathologie, UniversitätsSpital Zürich, Zürich Cellular and molecular characterization of IL-12-mediated tumor suppression Boyman Onur KFS 02672-08-2010 CHF 343,400. Dermatologische Klinik, UniversitätsSpital Zürich, Zürich Preclinical testing of interleukin-2-antibody complexes for tumor immunotherapy Brisken Cathrin KFS 02462-08-2009 CHF 331,200. NCCR Molecular Oncology, Institut suisse de recherche expérimentale sur le cancer (ISREC), Faculté des sciences de la vie, EPF de Lausanne, Lausanne Mechanisms of action of progesterone in the human breast Brown Steven A. KFS 02642-08-2010 CHF 240,100. Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Universität Zürich, Zürich The mechanism of cancer and circadian clock interactions and its usefulness in the design of therapeutic strategies Christofori Gerhard KLS 02535-02-2010 CHF 283,200. Institut für Biochemie und Genetik, Departement Biomedizin, Universität Basel, Basel The functional role of the transcription factors DIx2 and Lhx2 in epithelial-mesenchymal transition (EMT) and in malignant tumor progression Constam Daniel KFS 02487-08-2009 CHF 307,600. UPCDA, Institut suisse de recherche expérimentale sur le cancer (ISREC), Faculté des sciences de la vie, EPF de Lausanne, Lausanne Role of activin signalling in metastatic melanoma Dotto Gian-Paolo OCS 02361-02-2009 CHF 314,350. Département de biochimie, Faculté de biologie et de médecine, Université de Lausanne, Epalinges Tumor suppressing function of calcineurin/nfat in keratinocytes Dufour Jean-François KFS 02541-02-2010 CHF 202,200. Institut für klinische Pharmakologie, Universität Bern, Bern Hepatocarcinogenic roles of mtor, raptor and rapamycins in absence of Pten Gönczy Pierre KLS 02584-02-2010 CHF 197,000. UPGON, Institut suisse de recherche expérimentale sur le cancer (ISREC), Faculté des sciences de la vie, EPF de Lausanne, Lausanne Mechanisms of centrosome duplication: From model organism towards therapeutic opportunities Grassi Fabio KFS 02445-08-2009 CHF 144,000. Istituto di ricerca biomedicina (IRB), Bellinzona Purinergic signalling in the pathophysiology of central nervous system infiltration in T-cell leukemia

Grünberg Jürgen KFS 02546-02-2010 CHF 192,400. Zentrum für radiopharmazeutische Wissenschaften, ETH-PSI-USZ, Paul Scherrer Institut, Villigen Combinational therapy of ovarian cancer metastases expressing the L1 cell adhesion molecule (L1-CAM) based on radioimmunotherapy and growth inhibition Hall Jonathan KFS 02648-08-2010 CHF 226,000. Institut für pharmazeutische Wissenschaften, ETH Zürich, Zürich Targeting pre-let-7 biogenesis in cancer Hemmings Brian A. KFS 02714-08-2010 CHF 278,700. Friedrich Miescher Institut für biomedizinische Forschung (FMI), Basel Dissecting translation reveals therapeutic prospects for malignant gliomas 94 Hottiger Michael O. KLS 02396-02-2009 CHF 261,700. Institut für Veterinärbiochemie und Molekularbiologie, Universität Zürich, Zürich Multiplex analysis of the ionizing radiation-induced signalling network at the single cell level Huard Bertrand KFS 02464-08-2009 CHF 283,400. Département de pathologie et immunologie, Faculté de médecine, Université de Genève, Genève APRIL blockade for the treatment of multiple myeloma Hübscher Ulrich KLS 02339-02-2009 CHF 203,100. Institut für Veterinärbiochemie und Molekularbiologie, Universität Zürich, Zürich Regulation of base excision repair by human DNA polymerase 1 through posttranslational modification: degradation versus stabilization Huelsken Joerg KFS 02667-08-2010 CHF 344,700. UPHUE, Institut suisse de recherche expérimentale sur le cancer (ISREC), Faculté des sciences de la vie, EPF de Lausanne, Lausanne Stemness control in cancer stem cells Hynes Nancy KFS 02528-02-2010 CHF 183,100. Friedrich Miescher Institut für biomedizinische Forschung (FMI), Basel Reciprocal cross-talk between low-density lipoprotein receptor-related protein 1 and receptor tyrosine kinases: Implications for modulating in vitro and in vivo properties of breast tumor cells Janscak Pavel KLS 02344-02-2009 CHF 74,800. Institut für molekulare Krebsforschung, Universität Zürich, Zürich Study of the role of mismatch-repair proteins in the cellular response to DNA double-strand breaks Krek Wilhelm KFS 02690-08-2010 CHF 226,000. Institut für Zellbiologie, ETH Zürich, Zürich Roles of the URI oncoprotein in B-RAF-signaling and melanoma cancer cell proliferation Martinou Jean-Claude KLS 02370-02-2009 CHF 209,100. Département de biologie cellulaire, Faculté des sciences, Université de Genève, Genève Studies on the role of TRAIL as a tumor metastasis promoter Meraldi Patrick KFS 02707-08-2010 CHF 226,000. Institut für Biochemie, ETH Zürich, Zürich How does overexpression of the Aurora-A oncogene override the spindle checkpoint? Merdes Gunter KFS 02695-08-2010 CHF 116,700. Departement Biosysteme, ETH Zürich, Basel Systems biology of tumor suppression and malignancy in the model system Drosophila Michielin Olivier KFS 02555-02-2010 CHF 304,500. Molecular Modelling Group (MMG), Institut suisse de bioinformatique (ISB), Lausanne Rational design of anti-mart-1 TCR sequences for adoptive transfer immunotherapies Müller Anne KFS 02640-08-2010 CHF 293,700. Institut für molekulare Krebsforschung, Universität Zürich, Zürich The molecular pathogenesis of Helicobacter pylori-induced mucosa-associated lymphoid tissue (MALT) lymphoma: Analysis of the role of small regulatory RNAs in lymphomagenesis and high grade transformation

Münz Christian KFS 02652-08-2010 CHF 347,200. Institut für experimentelle Immunologie, Universität Zürich, Zürich Tumorigenesis and immune control of the Epstein Barr virus in vivo Ochsenbein Adrian F. KLS 02342-02-2009 CHF 320,450. Universitätsklinik für medizinische Onkologie, Inselspital, Bern Immunogenicity of chronic myeloid leukaemia stem cells Pertz Olivier KFS 02485-08-2009 CHF 333,000. Institut für Biochemie und Genetik, Departement Biomedizin, Universität Basel, Basel A slit/robo signalling pathway regulating contact mediated repulsion during cell migration: Implications of its deregulation for the acquisition of an invasive phenotype during breast cancer Petrova Tatiana KLS 02570-02-2010 CHF 198,300. Centre pluridisciplinaire d oncologie (CePO), Centre hospitalier universitaire vaudois (CHUV) et Université de Lausanne, Epalinges Lymphatic endothelial calcineurin/nfat signalling in tumor lymphangiogenesis and metastasis 95 Plückthun Andreas KFS 02448-08-2009 CHF 238,600. Biochemisches Institut, Universität Zürich, Zürich Tumor targeting of ErbB2 with designed ankyrin repeat proteins Pruschy Martin KFS 02551-02-2010 CHF 303,700. Labor für molekulare Radiobiologie, Klinik für Radio-Onkologie, UniversitätsSpital Zürich, Zürich Differential response to proton versus photon radiotherapy: Biological implications for new indications and combined treatment concepts Radtke Freddy KLS 02387-02-2009 CHF 316,700. UPRAD, Institut suisse de recherche expérimentale sur le cancer (ISREC), Faculté sciences de la vie, EPF de Lausanne, Lausanne The role of Notch and TSLPR signalling during skin cancer Renner Christoph KFS 02500-08-2009 CHF 194,500. Klinik und Poliklinik für Onkologie, Medizinbereich Innere Medizin-Onkologie, UniversitätsSpital Zürich, Zürich Inhibition of tumour growth by targeting cancer associated fibroblasts Ruiz i Altaba Ariel OCS 02359-02-2009 CHF 339,500. Département de génétique médicale et de développement, Faculté de médecine, Université de Genève, Genève Role and prevalence of hedgehog signalling in human colorectal cancer Santamaria Anna KFS 02657-08-2010 CHF 194,400. Departement Biozentrum, Universität Basel, Basel Control of chromosome segregation fidelity by the Ska complex, a key regulator of stable kinetochoremicrotubule attachments during mitosis Schär Primo KFS 02585-02-2010 CHF 237,500. Institut für Biochemie und Genetik, Departement Biomedizin, Universität Basel, Basel DNA repair, epigenetic stability, and CpG island hypermethylation in colorectal tumorigenesis Schorderet Daniel KFS 02565-02-2010 CHF 197,000. Institut de recherche en ophtalmologie (IRO), Sion Retinoblastoma: Understanding its development for better treatment Swartz Melody KFS 02696-08-2010 CHF 405,300. Institute of Bioengineering and Institute for Experimental Cancer Research, EPF de Lausanne, Lausanne Roles of tumor VEGF-C and CCL21 in immunological tolerance Thoma Nicolas OCS 02365-02-2009 CHF 186,300. Friedrich Miescher Institut für biomedizinische Forschung (FMI), Basel The molecular basis of the defense against skin cancer: Structural studies of the DDB1-DDB2-XPC/Rad23 UV-damage handover complex Thome-Miazza Margot KFS 02561-02-2010 CHF 198,300. Département de biochimie, Université de Lausanne, Epalinges Analysis of the role of the protease MALT1 in human lymphomas

Tschan Mario P. KFS 02486-08-2009 CHF 262,500. Medizinische Onkologie/Hämatologie, Departement für klinische Forschung, Universität Bern, Bern The importance of autophagy in normal and leukemic myelopoiesis Weller Michael KFS 02694-08-2010 CHF 195,700. Klinik für Neurologie, UniversitätsSpital Zürich, Zürich Angiogenesis and invasion in glioblastoma: The therapeutic options and risks of co-targeting VEGF and TGF-beta Widmann Christian KFS 02543-02-2010 CHF 205,300. Département de physiologie, Faculté de biologie et de médecine, Université de Lausanne, Lausanne The 317-326 sequence of RasGAP as potential anti-metastatic agent 96 Wymann Matthias Paul KFS 02680-08-2010 CHF 343,000. Institut für Biochemie und Genetik, Departement Biomedizin, Universität Basel, Basel Identification and modulation of targets to reprogram glioblastoma cancer stem cells Zaugg Kathrin KLS 02569-02-2010 CHF 78,000. Labor für angewandte Radio-Onkologie, UniversitätsSpital Zürich, Zürich Elucidating the role of the hypoxia-protective gene CPT1C (Carnitine Palmitoyl-transferase 1C) in carcinogenesis Zavolan Mihaela KFS 02477-08-2009 CHF 303,000. Departement Biozentrum, Universität Basel, Basel Identification of cancer-related targets of individual members of the mir-17~92 cluster of mirnas Approved bursaries in 2009/2010 Total funds allocated: CHF 722,132. Cornaz Sandrine MD-PhD 02607-06-2010 CHF 180,533. Mechanisms that regulate primary cell genetic reprogramming and differentiation by sarcoma-associated fusion genes (SAMW MD-PhD bursary) Zielort: Institut de pathologie, Centre hospitalier universitaire vaudois (CHUV), Lausanne Ecsedi Matyas MD-PhD 02431-06-2009 CHF 180,533. Regulation of the let-7 tumor suppressor microrna in development and cancer (SAMW MD-PhD bursary) Zielort: Labor Grosshans, Friedrich Miescher Institut für biomedizinische Forschung (FMI), Basel Essig Martin MD-PhD 02606-06-2010 CHF 180,533. Transition from paediatric to adult care for childhood cancer survivors (SAMW MD-PhD bursary) Zielort: Forschungsgruppe Kinder- und Jugendlichengesundheit, Institut für Sozial- und Präventivmedizin (ISPM), Universität Bern, Bern Özdemir Berna MD-PhD 02430-06-2009 CHF 180,533. Tumour-stroma interactions in prostate cancer bone metastasis (SAMW MD-PhD bursary) Zielort: Forschungsgruppe Urologie, Departement für klinische Forschung, Universität Bern, Bern

Basic biomedical research Presentation of approved research projects in 2009/2010 Aguet Michel Role of BCL9/BCL9L in regulating Wnt-mediated epithelial-mesenchymal transition, stem cell traits and drug sensitivity in Wnt-activated human cancers (KFS 02674-08-2010) Duration: 01.09.2010 01.09.2012 A major problem of anti-cancer therapies is tumour relapse, typically associated with resistance to therapy. Recent observations suggest that tumour cells with stem cell-like properties, including notably reduced susceptibility to common chemotherapeutic agents, are often at the origin of relapses. Our group recently reported that in a mouse model of colon cancer, inactivation of BCL9 proteins suppresses malignancy traits, including stem cell markers. Our current studies focus on validating the relevance of these observations for human colon cancer. Specifically, we will address to what extent inhibition of BCL9 results in attenuated stem cell properties and, most importantly, whether susceptibility to therapy might thereby get enhanced. The project should therefore contribute to establishing BCL9 proteins as targets for a novel therapy aimed at restoring responsiveness to therapy, and to justifying the search for small compound BCL9 inhibitors. Prof. Dr Michel Aguet Institut suisse de recherche expérimentale sur le cancer (ISREC) NCCR Molecular Oncology Faculté sciences de la vie EPF de Lausanne (EPFL) c/o Département de pathologie Rue du Bugnon 25 CH-1011 Lausanne Phone +41 (0)21 314 72 17 michel.aguet@epfl.ch Basler Konrad Characterization of the role of histone binding by the WnT signaling components Pygo2 in murine models of breast cancer and colon cancer (KFS 02443-08-2009) Duration: 01.01.2010 01.01.2013 Colon and breast cancer are two of the most common types of tumours. Dysregulation of the Wnt signalling cascade is known to underlie their formation. The goal of this project is to better understand the role played by Pygopus, a key component of the Wnt signalling pathway. It is now well accepted that decoding the marks found on histones is an essential part of the process that determines if expression of a gene is turned on or off. Histones are the proteins that together with DNA form chromatin the basis of our genome. We want to find out if Pygopus can act as a histone code reader and in this way contributes to the activation of the genetic program triggered by the Wnt signal. The insights gained from this study will provide important insights into how the Wnt signalling cascade contributes to colon and breast cancer progression and will open new avenues for the treatment of these cancers. Prof. Dr. Konrad Basler Institut für molekulare Biologie Universität Zürich Winterthurerstrasse 190 CH-8057 Zürich Phone +41 (0)44 635 31 10 basler@molbio.uzh.ch Becher Burkhard Cellular and molecular characterization of IL-12-mediated tumor suppression (KFS 02441-08-2009) Duration: 01.05.2010 01.05.2012 Immune cells (white blood cells) and their secreted signalling molecules play a critical role in tumour control and elimination. In a variety of tumour models, the signalling molecule interleukin-12 (IL-12) has been shown to repress tumour growth. Yet, IL-12 injection into the blood of human patients led to severe adverse effects, and therefore the development of IL-12 therapies has been halted. To this day, the molecular and cellular events of IL-12 have been ill-understood. By defining the mechanistic underpinnings of how IL-12 works, we shed light on how tumour cells and immune cells interact in general, and in particular we will enhance the therapeutic targeting of malignancies in humans. The tumouricidal activity of IL-12 was widely held to be mediated by two specific subsets of white blood cells, the natural killer cells and the T lymphocytes. However, we found that tumour suppression is mediated independently of these two subsets. Instead, we were able to demonstrate that IL-12 initiates powerful local anti-tumour immunity by stimulating a subset of lymphoid tissue inducer (LTi) cells. These cells seem to alter the blood vessels within the tumour mass in a way that allows immune cells to enter the tumour and actively fight it. Lastly, our findings also demonstrate that IL-12 should be injected directly into the tumour, thereby limiting the adverse effects observed after injection into the blood stream. Prof. Dr. Burkhard Becher Institut für experimentelle Immunologie Universität Zürich Y44-J92 (Office), J38/42 (Lab) Winterthurerstrasse 190 CH-8057 Zürich Phone +41 (0)44 635 37 03 Fax +41 (0)44 635 68 83 burkhard.becher@neuroimm.uzh.ch 97

98 Boyman Onur Preclinical testing of interleukin-2- antibody complexes for tumor immunotherapy (KFS 02672-08-2010) Duration: 01.02.2011 01.02.2014 Despite the use of improved treatment options, most patients with metastatic tumours die within a few years. This is also the case for metastatic malignant melanoma, a deadly skin tumour. Apart from chemotherapeutic regimens, the use of interleukin 2 (IL-2) immunotherapy in the treatment of metastatic melanoma has shown promising results. IL-2 belongs to the family of cytokines that are produced by the body s defence system (immune system) and is able to activate cytotoxic T lymphocytes (also called CD8 + T cells). Activated CD8 + T cells are able to attack and kill tumour cells. For these properties, IL-2 was used at high doses in metastatic melanoma, and it led to a long-term survival of about 13 % of patients for over twenty years, which is considerable, given the survival rate of below 5 % within five years in untreated patients. However, IL-2 immunotherapy can lead to serious side effects, such as lung oedema or liver damage, which is the reason why this treatment is not used more frequently. Recently, we showed in an animal model that IL-2/anti- IL-2 antibody complexes are more efficient against malignant melanoma and show fewer (or no) side effects. Based on these promising results in a mouse model of melanoma, we will examine the effects of human IL-2/anti- IL-2 antibody complexes on the activation of human CD8 + T cells against melanoma cells. To this end, we will use humanized mice, which carry human immune cells, including CD8 + T cells. Testing of IL-2/anti-IL-2 antibody complexes on human T cells using humanized mice is a crucial step towards being able to proceed to clinical studies. Prof. Dr. Onur Boyman Dermatologische Klinik UniversitätsSpital Zürich Gloriastrasse 31 CH-8091 Zürich Phone +41 (0)44 255 25 60 onur.boyman@usz.ch Brisken Cathrin Mechanisms of action of progesterone in the human breast (KFS 02462-08-2009) Duration: 01.02.2010 01.02.2013 The mechanisms by which the pregnancy hormone progesterone acts on the human breast and contributes to breast carcinogenesis are poorly understood, because we lack adequate models to study them. Our work in the mouse model revealed that progesterone acts on a subset of cells in the milk ducts and induces them to secrete a protein called RANKL that in turn acts on neighbouring cells and makes them proliferate. We are developing a novel approach using fresh tissue from reduction mammoplasties to preserve the microenvironment and essential interactions between the cells to identify the mediators of progesterone in the human breast. New drugs that interfere with progesterone or RANKL signalling are already in clinical trials for different purposes, and many inhibitors of specific signalling pathways have been developed. The insights gained will be instrumental to determine whether progesterone indeed has cancer-promoting effects in the human breast. As a consequence, drugs blocking progesterone receptor (PgR) signalling and/ or its mediators may be useful as novel therapeutic and preventive strategies in the management of breast cancer. Prof. Dr Cathrin Brisken Institut suisse de recherche expérimentale sur le cancer (ISREC) NCCR Molecular Oncology Faculté des sciences de la vie EPF de Lausanne (EPFL) SV2.832 Station 19 CH-1015 Lausanne Phone +41 (0)21 693 07 81 Fax +41 (0)21 693 07 40 cathrin.brisken@epfl.ch Brown Steven A. The mechanism of cancer and circadian clock interactions and its usefulness in the design of therapeutic strategies (KFS 2642-08-2010) Duration: 01.01.2011 01.01.2014 The circadian clock and the cell cycle are cell autonomous processes. The interaction between them is complex; the clock gates the cell cycle but ticks on even if the cell cycle is halted. Perturbations of the clock and the cell cycle can lead to cancer. In our project, we want to elucidate how the clock interacts with the cell cycle and then use this knowledge to improve the timing and thereby the efficiency of radio-therapeutic treatment regimes in models of brain tumours. Tumour clocks and/or clocks in the tissue surrounding the tumour could play a major role in tumour growth and prognosis for the patient. Thus, our goal is to understand the interaction of the various clocks with the cell cycle that determines tumour growth, and with this knowledge determine an optimal timing of treatment. We propose first to analyze circadian clock function in multiple different tumour cell lines to understand how the circadian clock is affected by oncogenic transformation. We will then test synthetically engineered clock-containing and clock-less tumours for growth in mice with or without circadian clocks to understand the contributions of clocks in the tumour and in the organism to tumour growth. Finally, we will treat these clock-containing and clock-less tumours radio-therapeutically to assess the contribution of clock function in both tumour and host to treatment outcome. Our results especially the results of the therapeutic models could lead to an improved efficacy of existing patient treatments by modifying already existing treatment regimes. Prof. Dr. Steven A. Brown Institut für Pharmakologie und Toxikologie Medizinische Fakultät Universität Zürich Winterthurerstrasse 190 CH-8057 Zürich Phone +41 (0)44 635 59 99 Fax +41 (0)44 635 57 07 steven.brown@pharma.unizh.ch

Christofori Gerhard The functional role of the transcription factors Dlx2 and Lhx2 in epithelialmesenchymal transition (EMT) and in malignant tumor progression (KLS 02535-02-2010) Duration: 01.09.2010 01.09.2013 The actual cause of death of most patients with cancer is due to metastasis. Malignant cancer cells leave their primary tumours, invade blood vessels and disseminate throughout the body to seed metastasis in distant organs. In this project, we investigated the functional contribution of the transcription factors Lhx2 and Dlx2 to metastasis. We found that both factors regulate genes that are critically required for cancer cell migration and metastasis formation. Lhx2 appears to directly regulate genes stimulating cell migration and invasion, whereas Dlx2 modulates the expression of genes required for cell survival during the metastatic process. Currently, we are identifying the genes that are regulated by Lhx2 and Dlx2 and investigating their functional contribution to cancer metastasis. The elucidation of the regulatory circuits underlying the metastatic process is a prerequisite for the development of innovative therapy to prevent cancer metastasis and thus patients death. Prof. Dr. Gerhard Christofori Institut für Biochemie und Genetik Departement Biomedizin Universität Basel Mattenstrasse 28 CH-4058 Basel Phone +41 (0)61 267 35 62 Fax +41 (0)61 267 35 66 gerhard.christofori@unibas.ch

100 Constam Daniel Role of activin signalling in melanoma metastasis (KFS 02487-08-2009) Duration: 01.02.2010 01.02.2013 Malignant melanomas arise from the transformation of pigment cells. These aggressive tumours are characterized by a poor prognosis, since the available treatments at best afford transient improvement. Cell proliferation and the synthesis of UV-absorbing melanin in pigment cells are governed by specific nuclear proteins that are themselves regulated by extracellular factors. Thus, other skin cells can supply themselves with pigment according to their needs. However, in the course of tumour progression, melanomas frequently learn how to produce these or similar signals by themselves. One of these signalling molecules is activin. To elucidate the role of activin during melanoma growth and metastasis, we are comparing the behaviour and tumourigenic potential of cell lines from a human melanoma that spontaneously progressed from an activin-negative to an activin-producing state, and we are manipulating activin signalling to determine which of its target genes may influence tumour progression. Prof. Dr Daniel Constam Institut suisse de recherche expérimentale sur le cancer (ISREC) Faculté des sciences de la vie EPF de Lausanne (EPFL) SV-ISREC-UPCDA SV 2837 Bâtiment SV, Station 19 Chemin des Boveresses 155 CH-1015 Lausanne Phone +41 (0)21 693 07 41 daniel.constam@epfl.ch Dotto Gian-Paolo Tumor suppressing function of calcineurin/nfat in keratinocytes (OCS 02361-02.2009) Duration: 1.10.2009 30.09.2012 Squamous cell carcinomas have a very high incidence in the human population, encompassing skin, oral and esophageal cancer, squamous (bronchial) lung carcinoma and carcinoma of the cervix and other parts of the urogenital system. A distinguishing feature of these tumours is their high level of heterogeneity, with self-renewing cell populations admixed with cells at different stages of differentiation. Important mechanisms involved in restraining cells with oncogenic potential are the induction of cellular senescence and/or differentiation. Counteracting these failsafe mechanisms are conditions of perturbed tissue homeostasis, such as those resulting from wound healing or inflammation. The immune system is also thought to play a major role in preventing or limiting tumour spread. Calcineurin is the only known serine/threonine phosphatase under calcium/calmodulin control and key regulator of the immune system. In the clinics, treatment of patients with calcineurin-inhibitory drugs like cyclosporin A and FK506 to prevent graft rejection dramatically increases the risk of cutaneous squamous cell carcinoma (SCC), which are a major cause of death after organ transplants. The main goal of this project is to test whether, in parallel with its function in the immune system, calcineurin/nfat signalling plays an intrinsic role in keratinocyte/scc tumour suppression. Clinically, we will validate the findings by analysis of a large cohort of cutaneous SCCs at various stages of malignancy in the general patient population versus patients under treatment with calcineurin inhibitors. Prof. Dr Gian-Paolo Dotto Département de biochimie Faculté de biologie et de médecine Université de Lausanne Chemin de Boveresses 155 CH-1066 Epalinges Phone +41 (0)21 692 57 20 Fax +41 (0)21 692 57 05 paolo.dotto@unil.ch Dufour Jean-François Hepatocarcinogenic roles of mtor, raptor and rapamycins in absence of Pten (KFS 02541-02-201) Duration: 01.08.2010 01.08.2013 Hepatocellular carcinoma is a tumour of worldwide significance: a) it is the fifth most common tumour; b) it is the third leading cause of cancer-related death; and c) its incidence has doubled in the last 2 decades. The PI(3)K/ AKT/mTOR pathway is activated in about half of the cases of hepatocellular carcinoma. mtor forms two enzymatic complexes with other proteins: The mtor complex 1 is downstream of AKT and regulates protein synthesis; the mtor complex 2 is upstream of AKT and activates AKT. Clinical trials testing drugs inhibiting the mtor complex 1 as antitumoural agents are underway. Concerns exist: 1) that inhibition of mtor in a liver with down-regulated PTEN may lead to hepatocyte attrition and recruitment of progenitor cells; and 2) that rapamycins have effects additional to the well characterized inhibition of mtorc1. We will compare mice with genetic ablation of the mtor complex 1 (lacking raptor) with mice without mtor as well as with mice treated with an mtor inhibitor. A better appreciation for the elusive role of these 2 complexes in the development of hepatocellular carcinoma will be partly elucidated by this research. Prof. Dr. Jean-François Dufour Institut für klinische Pharmakologie Universität Bern Murtenstrasse 35 CH-3010 Bern Phone +41 (0)31 632 09 00 Fax +41 (0)31 632 49 97 jf.dufour@ikp.unibe.ch

Gönczy Pierre Mechanisms of centrosome duplication: From model organism towards therapeutic opportunities (KLS 02584-02-2010) Duration: 01.09.2010 01.09.2013 The centrosome comprises two centrioles and is the principal microtubule organizing centre of animal cells. Centrosome duplication occurs solely in proliferating cells and is required for proper cell division and genome integrity. Cancer cells often exhibit aberrations in centrosome number or structure. Therefore, centrosome duplication offers significant therapeutic opportunities in the fight against cancer. Here, we propose to combine the strengths of two experimental systems, C. elegans and human cells, to gain further insights into the mechanisms of centrosome duplication. We will focus on SAS-6/HsSAS-6 and SAS-4/ CPAP, two evolutionarily conserved proteins critical for this process. We will notably investigate centriole inheritance and the impact of aberrant centriole number and structure in a stem cell lineage of C. elegans. Moreover, we will undertake further analysis of HsSAS-6 and CPAP in human cells and identify interacting partner proteins. In the end, we will seek to identify chemical compounds that preferentially target proliferating cells with aberrant centrosomes, as is the case of many cancer cells. Prof. Dr Pierre Gönczy Institut suisse de recherche expérimentale sur le cancer (ISREC) Faculté des sciences de la vie EPF de Lausanne (EPFL) SV 1526, Station 19 CH-1015 Lausanne Phone +41 (0)21 693 07 11 pierre.gonczy@epfl.ch Grassi Fabio Purinergic signalling in the pathophysiology of central nervous system infiltration in T-cell leukemia (KFS 02445-08-2009) Duration: 01.01.2010 01.01.2013 T-cell acute lymphoblastic leukaemia (T-ALL) is characterized by increased risk of central nervous system (CNS) infiltration by leukaemic cells. T-ALL patients at increased risk of CNS relapse receive, in addition to intensified intrathecal chemotherapy, prophylactic cranial irradiation, which can cause severe complications. Therefore, therapies with improved efficacy and reduced side-effects remain a long-term objective in the treatment of CNS relapse in T-ALL. Adenosine 5 -triphosphate (ATP) constitutes the source of chemical energy for the majority of cellular functions. However, ATP is also released in the extracellular space and activates purinergic receptors in the plasma membrane, known as P2. The aim of this project is to understand the molecular bases of the extended survival and reduced brain infiltration we observed in immunodeficient mice adoptively transferred with T-ALL cells upon treatment with a pharmacological antagonist of purinergic P2X receptors, periodate-oxidized ATP. Dr. Fabio Grassi Istituto di ricerca in biomedicina (IRB) Via Vincenzo Vela 6 CH-6500 Bellinzona Phone +41 (0)91 820 03 23 fabio.grassi@irb.unisi.ch Grünberg Jürgen Combinational therapy of ovarian cancer metastases expressing the L1 cell adhesion molecule (L1-CAM) based on radioimmunotherapy and growth inhibition (KFS 02546-02-2010) Duration: 01.08.2010 01.08.2013 The aim of this project is to expand and improve the treatment options for metastatic ovarian cancer. This will be achieved through the use of the chimerized anti-l1 cell adhesion molecule (L1-CAM) antibody chce7 in conjunction with other treatment modalities. Histological examination of tumour tissues showed that 79 % of all ovarian carcinomas overexpress the L1-CAM. Here we will use therapeutic radionuclides (lutetium-177, copper-67), which are particularly suitable for the irradiation of small metastases. Different combinations of radioimmunotherapy (RIT) with kinase inhibitors and chemotherapy (carboplatin, paclitaxel) and anti-l1 antibody-mediated tumour growth inhibition will be investigated in ovarian cancer xenograft models to find an optimal postoperative treatment regimen. Dr. Jürgen Grünberg Bereich Biologie und Chemie Paul Scherrer Institut Zentrum für radiopharmazeutische Wissenschaften ETH-PSI-USZ OIPA 10A CH-5232 Villigen Phone +41(0)56 310 28 48 Fax +41(0)56 310 28 49 juergen.gruenberg@psi.ch Hall Jonathan Targeting pre-let-7 biogenesis in cancer (KFS 02648-08-2010) Duration: 01.02.2011 01.02.2013 The dysregulation of microrna expression by loss- or gainof-function is linked to several human cancers. MicroRNAs therefore represent a new class of therapeutic targets. The function of mature micrornas may be inhibited in vivo by chemically-modified single-stranded RNAs in the cell. For example, recent publications showed the importance of the interaction between Lin28 and the let-7 microrna precursor in the development of various cancers. Here we propose to find molecular inhibitors of this interaction by targeting the RNA precursor, the Lin28 protein or the RNA-protein complex. We will use a multidisciplinary approach with small-molecule assay combined with a structural study to optimize the interactions and biological assays to assess their effects in vitro and in vivo. From 101

102 this study we will examine the therapeutic potential of let-7 microrna precursors and other micrornas in the development of cancer. Prof. Dr. Jonathan Hall Institut für pharmazeutische Wissenschaften ETH Zürich HCI H 437 Wolfgang-Pauli-Strasse 10 CH-8093 Zürich Phone +41 (0)44 633 74 35 Fax +41 (0)44 633 13 69 jonathan.hall@pharma.ethz.ch Hemmings Brian A. Dissecting translation reveals therapeutic prospects for malignant gliomas (KFS 02714-08-2010) Duration: 01.03.2011 01.03.2014 Glioblastoma multiforme (GBM) is the most common and aggressive brain tumour entity, with a median survival of approximately one year. The proposed study aims to uncover novel molecular mechanisms regulating gene expression at the translation level triggered by deregulated signalling pathways. Further, therapeutic perspectives of the results obtained will be validated in the GBM animal models. Understanding of the novel molecular mechanisms that regulate selective translation will not only explain principles underlying rapid signalling responses controlling translation and its phenotypical consequences but will also allow proposal and development of molecular strategies for therapeutic interference for malignant brain tumours. Dr. Brian A. Hemmings Friedrich Miescher Institut für biomedizinische Forschung (FMI) Maulbeerstrasse 66 CH-4058 Basel Phone +41 (0)61 697 48 72 brian.hemmings@fmi.ch Hottiger Michael O. Multiplex analysis of the ionizing radiation induced signaling network at the single cell level (KLS 02396-02-2009) Duration: 01.05.2009 01.05.2012 Every cell is exposed to genotoxic stresses such as radiation or chemicals that can cause harmful and deleterious mutations in the genome. Cells have evolved an intricate regulatory protein network to detect and repair DNA damage with the aim to maintain genomic stability and thus prevent tumourigenesis. Until now, technical and practical limitations prohibited comprehensive deciphering of this regulatory network. The goal of this study is to measure, with reverse protein micro arrays, simultaneously changes and modifications of hundreds of proteins in human cells (fibroblasts) upon exposure to genotoxic stress. Thereby, we will define key players of the genotoxic signalling network and predict functional interaction between different signalling components, which will be experimentally probed further for their function and connections. The results of this project will provide a comprehensive picture of a cell s response to genotoxic stress and the opportunity to improve our possibilities to detect and treat tumours. Prof. Dr. Michael O. Hottiger Institut für Veterinärbiochemie und Molekularbiologie Universität Zürich Winterthurerstrasse 190 CH-8057 Zürich Phone +41 (0)44 635 54 74 hottiger@vetbio.uzh.ch Huard Betrand APRIL blockade for the treatment of multiple myeloma (KFS-02464-08-2009) Duration: 01.05.2010 01.05.2013 Multiple myeloma (MM) is a tumour arising after transformation of antibody-producing plasma cells residing in the bone marrow (BM). There are about 450 new MM cases yearly in Switzerland. MM develops in BM and induces severe bone lesions. Nowadays a high response rate (95 %) in MM patients is achieved by the introduction of new chemotherapeutic drugs and their combination. Unfortunately, MM remains an incurable disease, due to uncontrolled relapse events, even when heavy treatment such as BM transplantation is performed. Current treatments are not highly specific to MM cells. However, the exclusive MM growth in BM revealed that BM must contain MM specific growth factor(s). Identifying them will lead to new targets for MM treatment. In the laboratory, we have recently observed that the BM is constitutively rich in a molecule called a proliferation-inducing ligand (APRIL). The physiological function of APRIL is to support long-term survival of plasma cells in BM, by this means maintaining our immune antibody memory. All these observation render APRIL a good candidate for a key MM growth factor. Aim of the study To test whether antibody-mediated APRIL blockade induces MM regression. Methods One major problem in MM research is the lack of an appropriate animal model. In collaboration with a Norwegian group, we created a mouse model highly relevant to the human pathology. The cell that we isolated, called MOPC-315BM, develops actively in BM after intravenous injection and leads to paralysis and death. In addition, we generated the first blocking antibody against mouse APRIL. In this research project, we plan to test whether APRIL blockade impairs MOPC-315BM development.

Patients perspectives In the case that we observe an inhibition of MOPC-315BM development by APRIL blockade, we will be able to quickly generate a similar antibody reacting with human APRIL. This antibody could be tested in MM patients. This will lead to a highly specific treatment targeting a growth factor used by MM cells. Dr Bertrand Huard Département de pathologie et immunologie Faculté de médecine Université de Genève 1, rue Michel-Servet CH-1211 Genève 4 Phone +41 (0)22 379 58 11 Fax +41 (0)22 379 57 46 bertrand.huard@unige.ch Hübscher Ulrich Regulation of base excision repair by human DNA polymerase l through posttranslational modifications: Degradation versus stabilization (KLS 02339-02-2009) Duration: 01.04.2009 01.04.2011 The maintenance of genetic stability is of crucial importance for any form of life. The genetic material, the DNA itself, is highly reactive and is constantly attacked by endogenous factors and is also easily altered by intracellular processes such as oxidation. The base guanine as 8-oxo- G is recognized as one of the most important oxidative DNA lesions because of its prevalence in DNA and its mutagenic potential in aging, tumourigenesis and neurodegenerative diseases. We identified that DNA polymerase l can correctly incorporate C opposite 8-oxo-G and identified the initial steps of how this protein is regulated in the cell. In particular it is stabilized during cell cycle progression, enabling proper repair of damaged DNA. With this project we would like to understand the molecular mechanisms of DNA polymerase l regulation during the cell cycle and thus investigate the role of the two post-translation modifications phosphorylation and ubiquitination. Prof. Dr. Ulrich Hübscher Institut für Veterinärbiochemie und Molekular biologie Universität Zürich Winterthurerstrasse 190 CH-8057 Zürich Phone +41 (0)44 635 54 72 Fax +41 (0)44 635 68 40/5904 hubscher@vetbio.uzh.ch Huelsken Joerg Stemness control in cancer stem cells (KFS 02667-08-2010) Duration: 01.01.2011 01.01.2014 As the cellular target for initiation of cancerogenesis, we and other laboratories recently identified normal, tissuespecific stem cells. These stem cells usually drive the continuous replenishment of tissues. Similarly, also tumours contain a small population of cancer stem cells that are responsible for formation and maintenance of the cancer. We were able to show that the Wnt signalling pathway controls essential stem cell properties, such as their apparent unlimited proliferation potential in normal and cancer tissues (Malanchi et al., Nature 2008). We now want to understand in more detail how Wnt signalling controls this process and will study the components of the epigenetic control of stem cell identity and mechanisms of their regulation. Our results will aid understanding of the fundamental processes that control tumour maintenance and will allow development of better targeted approaches for the elimination of such cancer stem cells. Prof. Dr Joerg Huelsken UPHUE Institut suisse de recherche expérimentale sur le cancer (ISREC) Faculté des sciences de la vie EPF de Lausanne (EPFL) SV 2823 (Bâtiment SV) Station 19 CH-1015 Lausanne Phone +41 (0)21 693 07 52 Fax +41 (0)21 693 07 70 joerg.huelsken@epfl.ch Hynes Nancy Reciprocal cross-talk between lowdensity lipoprotein receptor-related protein 1 and receptor tyrosine kinases: Implications for modulating in vitro and in vivo properties of breast tumor cells (KFS 02528-02-2010) Duration: 01.08.2010 01.08.2012 Low-density lipoprotein receptor-related protein 1 (LRP1) is a 600 kda transmembrane protein that binds more than 40 distinct ligands, many of which are involved in regulation of extracellular protease activity. LRP1 is also crossregulated by various receptor tyrosine kinases (RTK). Ligand binding to LRP1 stimulates intracellular signalling pathways by unknown mechanisms. We have shown that binding of the serpin protease nexin-1 (PN-1) to LRP1 in mammary cancer cell lines stimulates the ERK pathway, regulates MMP-9 expression and, in vivo, is responsible for the metastatic spread of a breast cancer model to the lungs. Based on this, the goals are: 1) in vitro experiments analyzing cross-talk between LRP1 and RTKs; 2) in vivo studies on metastatic breast tumour models, targeting PN1 alone or in combination with RTK inhibitors. Prof. Dr. Nancy Hynes Friedrich Miescher Institut für biomedizinische Forschung (FMI) Maulbeerstrasse 66 CH-4058 Basel Phone +41 (0)61 697 81 07 Fax +41 (0)61 697 39 76 nancy.hynes@fmi.ch 103

104 Janscak Pavel Study of the role of mismatch repair proteins in the cellular response to DNA double-strand breaks (KLS 02344-02-2009) Duration: 01.07.2009 01.07.2011 DNA damage is a frequent event in the life of a cell. Failure to repair DNA damage can lead to cell death, and inaccurate DNA repair can give rise to genomic instability, which promotes the onset of cancer in mammals. The most deleterious form of DNA damage is DNA doublestrand break (DSB). In eukaryotic cells, two mechanistically distinct pathways are known to efficiently repair DSBs: non-homologous end joining and homologous recombination. However, molecular mechanisms underlying these DNA repair pathways are not completely understood. Our recent experiments with human cells revealed that proteins involved in the initiation of post-replicative mismatch repair (MMR), such as MSH2, MSH3, MSH6 and MLH1, accumulate at sites of chromosomal DSBs generated by UVA laser. Ongoing research in our laboratory aims to gain insight into the function of MMR proteins at the sites of DNA damage in human cells. The project utilizes various cell biology methods in combination with laser micro-dissection technology and immunofluorescence microscopy. Using RNA interference, we intend to identify the DNA repair factors that are required for the recruitment of MMR proteins to the sites of DSBs. DNA repair capacity of cells depleted for the individual MMR proteins will be assessed using chromosomallybased reporters for specific DSB repair pathways and by testing sensitivity of depleted cells to DNA damaging agents. Our preliminary data indicate that the MMR proteins accumulate at DSBs in a manner dependent on MRE11 and CtIP, which are involved in the initiation homologous recombination. Germline mutations in the MLH1, MSH2 and MSH6 genes are the major cause of hereditary non-polyposis colon cancer. It is anticipated that our study will advance understanding of the molecular events leading to this most common form of inherited colon cancer. Dr. Pavel Janscak Institut für molekulare Krebsforschung Universität Zürich Winterthurerstrasse 190 CH-8057 Zürich Phone +41 (0)44 635 34 70 pjanscak@imcr.uzh.ch Krek Wilhelm Roles of the URI oncoprotein in B-RAF-signaling and melanoma cancer cell proliferation (KFS 02690-08-2010) Duration: 01.02.2011 01.02.2013 Malignant melanoma ( black skin cancer ) is one of the most aggressive cancers. Prognosis for advanced stages is dismal due to a lack of efficient systemic therapies, with classical cytotoxic chemotherapy being particularly inefficient. Elucidating the molecular and cell biological bases of melanomagenesis is therefore of prime importance and has already led to findings that have been translated successfully to the clinics. A central player in melanomagenesis is BRAF V600E, which is a constitutively active mutant form of the BRAF kinase, a component of the RAS/RAF/MEK/ ERK-signaling cascade. BRAF V600E is found in about 70 % of all melanomas, and mouse models demonstrated its oncogenic potential. Selective BRAF V600E inhibitors have been developed and their therapeutic efficiency in first clinical trials is promising. However, after some months clinical resistance develops, and therefore new therapeutic strategies are still very much needed. BRAF V600E provokes overactive RAS/RAF/MEK/ERK-signalling leading to un con trolled cellular proliferation. Several mechanisms regulate the activity of this pathway at multiple levels. Particularly important in the negative regulation of pathway activity are negative feedback systems mediated by phosphatases that dampen overactive signalling. That might also be one of the reasons why the BRAF V600E alone does not suffice for malignant transformation, but secondary changes ( second hits ) are a prerequisite. We recently discovered a novel phosphatase (PP)1-dependent negative feedback system that acts to restrain S6K1 survival signalling in response to nutrient and growth factor stimulation. Moreover, PP1 is a target of oncogenic alterations that disable PP1-mediated feedback inhibition on survival signalling in different human cancers. In this project we are testing whether this PP1-dependent feedback system also acts on the RAS/RAF/MEK/ERK pathway and is oncogenically targeted in human melanoma. In this work we are combining human tissue microarrays (TMA), quantitative phosphoproteome analyses, RNA interference and mouse models of melanomagenesis. From these studies, we expect to discover novel regulatory mechanisms of oncogenic BRAF V600E signalling and of RAS/RAF/MEK/ERK-signalling in general. Prof. Dr. Wilhelm Krek Institut für Zellbiologie ETH Zürich HPM F42 Schafmattstrasse 18 CH-8093 Zürich Phone +41 (0)44 633 34 47 Fax +41 (0)44 633 13 57 wilhelm.krek@cell.biol.ethz.ch

Martinou Jean-Claude Studies on the role of TRAIL as a tumor metastasis promoter (KLS 02370-02-2009) Duration: 01.11.2009 01.11.2011 TRAIL is a protein that is able to trigger apoptosis of cancer cells but is inefficient in killing non tumour cells, hence its interest in cancer treatment. We noticed that TRAIL can induce apoptosis of various cancer cells but is unable to kill cells that display a dysfunctional mitochondrial pathway of apoptosis. In this case, TRAIL stimulates cell detachment from their substrate, which raises the possibility that administration of TRAIL for cancer treatment could lead to metastatic dissemination of the tumour. This is the hypothesis that we are currently testing using mice in which tumours are implanted and treated with TRAIL. Our results may have consequences for cancer treatment with TRAIL and may limit its administration to tumours with a functional apoptosis mitochondrial pathway. Prof. Dr Jean-Claude Martinou Département de biologie cellulaire Faculté des sciences Université de Genève 30, quai Ernest-Ansermet CH-1211 Genève 4 Phone +41 (0)22 379 64 43 Fax +41 (0)22 379 64 42 jean-claude.martinou@unige.ch Merdes Gunter Systems biology of tumor suppression and malignancy in the model system Drosophila (KFS 02695-08-2010) Duration: 01.03.2011 01.03.2014 To study the development of cancer, researchers use cells from patients and animals like the mouse or the fruit fly. At first sight, fruit flies seem inappropriate based on obvious differences between fruit flies and us. However, it was discovered not only that are we very similar even in the number of genes but also that important findings about the development of cancer are directly transferable from fruit flies to humans. Accordingly, we plan to identify all the genes involved in tumour suppression in the fruit fly by systematically switching on and off single genes and by studying the interconnectivity of the identified cancer genes. It is our long-term goal to recognize new therapeutic strategies in humans based on these results. Dr. Gunter Merdes Departement Biosysteme ETH Zürich Mattenstrasse 26 CH-4058 Basel Phone +41 (0)61 387 31 24 Fax +41 (0)61 387 39 94 gunter.merdes@bsse.ethz.ch 105 Meraldi Patrick How does overexpression of the Aurora A oncogene override the spindle checkpoint? (KFS 02707-08-2010) Duration: 01.06.2011 01.06.2013 Taxol is one of the most potent cancer drugs available. It is a spindle poison that perturbs orderly cell division. Cells possess a checkpoint that blocks cell division in the presence of such defects, which is why Taxol treatments block the uncontrolled growth of cancer cells. Unfortunately, many cancer patients are resistant to Taxol, as they overexpress the Aurora A protein, a condition that disrupts the cell division checkpoint. Although we have learned a lot about the functions of Aurora A in normal cells, we still do not understand how the cell division checkpoint is impaired by the pathological overexpression of Aurora A. Our goal is to understand this mechanism by identifying the proteins that interact specifically with overexpressed Aurora A. This knowledge will form the basis for new drugs that could prevent such pathological interactions with Aurora A and abolish Taxol resistance in cancer patients. Prof. Dr. Patrick Meraldi Institut für Biochemie ETH Zürich Schafmattstrasse 18 CH-8093 Zürich Phone +41 (0)44 632 63 47 Fax +41 (0)44 632 15 91 patrick.meraldi@bc.biol.ethz.ch Michielin Olivier Rational design of anti-mart-1 TCR sequences for adoptive transfer immunotherapies (KFS 02555-02-2010) Duration: 01.03.2010 01.03.2013 T-cell receptors (TCRs) control the specificity and efficacy of the cellular specific immune system by recognizing foreign and abnormal antigens presented by the MHC molecules. However, their low affinity constitutes a critically limiting factor of tumour immunity. We therefore designed a new structure-based computational approach using free energy calculations to rationally design TCRs. By controlling the mutations structural and functional effect, the approach is likely to suggest TCRs with optimal activity and lower risk of cross-reactivity. We engineered TCRs specific for NY-ESO-1, a cancer testis antigen peptide expressed not only in melanoma but also in several other types of cancers. We obtained specific antigens with controlled affinities up to 160-fold higher than that of the wild type TCR. Corresponding engineered T-cells exhibited improved killing of melanoma cell lines and better proliferative capacity, thus paving the road to clinical trials. We are now using this technique to design TCRs specifically recognizing the MART-1 antigen, which is expressed by melanoma cells. Prof. Dr Olivier Michielin Molecular Modelling Group (MMG) Institut suisse de bioinformatique (ISB) Quartier Sorge Bâtiment Génopode Chemin des Boveresses 155 CH-1015 Lausanne Phone +41 (0)21 692 40 53 Olivier.michielin@unil.ch

106 Müller Anne The molecular pathogenesis of Helicobacter pylori-induced mucosa-associated lymphoid tissue (MALT) lymphoma: Analysis of the role of small regulatory RNAs in lymphomagenesis and high grade transformation (KFS 02640-08-2010) Duration: 01.11.2010 01.11.2013 We are studying the pathogenesis of mucosa-associated lymphoid tissue lymphomas, which arise in chronically inflamed tissues. The most common site of MALT lymphomagenesis is the inflamed gastric mucosa of Helicobacter pylori-infected individuals. Whereas gastric MALT lymphoma is a relatively indolent disease, its high grade-transformed disease counterpart, gastric diffuse large B-cell lymphoma (DLBCL), represents a clinically relevant disease entity with poor prognosis. Through the use of patient material we have identified a small regulatory RNA (called a microrna) that may play a role in high grade transformation. mir-34a was found to be transcriptionally repressed in all examined cases of high grade but not of low grade gastric lymphoma. The forced expression of mir-34a very efficiently blocks proliferation of two high grade diffuse large B-cell lymphoma cell lines, suggesting a tumour suppressive role of mir-34a in this disease entity. We have further identified a mir-34a target with a likely functional significance in gastric lymphomagenesis, the haematopoietic oncoprotein FoxP1. We now plan to investigate in a larger set of DLBCL cells lines as well as in a wellestablished DLBCL xenograft model whether mir-34a indeed has tumour suppressive properties and its target FoxP1 has oncogenic properties in MALT lymphoma. Specifically, we postulate that the silencing of mir-34a and the resulting overexpression of FoxP1 promote high grade transformation of gastric MALT lymphoma. Prof. Dr. Anne Müller Institut für molekulare Krebsforschung Universität Zürich Winterthurerstrasse 190 CH-8057 Zürich Phone +41 (0)44 635 34 74 Fax +41 (0)44 635 34 84 mueller@imcr.uzh.ch Münz Christian Tumorigenesis and immune control of the Epstein Barr virus in vivo (KFS-02652-08-2010) Duration: 01.02.2011 01.02.2014 A substantial proportion of human tumours are caused by viruses. Among these, Epstein Barr virus (EBV) induces lymphomas and carcinomas. Mutations in EBV have been observed in patients with aggressive lymphomas. This project is designed to understand tumourigenesis and immune control of these mutant EBV viruses. For this purpose mice with reconstituted human immune system components will be used, since EBV infects only human cells. A better understanding of the mechanisms by which mutant EBV causes aggressive tumours will reveal interesting aspects of EBV immunobiology, aid diagnostic assessment of risks associated with mutant EBV infection in patients and provide therapeutic avenues for aggressive EBV-associated malignancies. Prof. Dr. Christian Münz Institut für experimentelle Immunologie Universität Zürich Winterthurerstrasse 190 CH-8057 Zürich Phone +41 (0)44 635 37 16 Fax +41 (0)44 635 68 83 christian.muenz@uzh.ch Ochsenbein Adrian F. Immunogenicity of chronic myeloid leukaemia stem cells (KLS 02342-02-2009) Duration: 01.01.2010 01.01.2013 Chronic myeloid leukaemia (CML) is a clonal myeloproliferative disorder resulting from the neoplastic transformation of a haematopoietic stem cell. Consequently, characterizing the leukaemia stem cell (LSC) is a key to understanding leukaemia pathogenesis and to developing more effective therapeutic regimens. However, LSC are selectively resistant to various forms of therapy, including imatinib, irradiation or cytotoxic drugs. We established a murine model of a CML-like disease by retroviral transduction of bone marrow stem cells expressing the onocogenes BCR/ABL. In this model we are studying the role of CD27 on LSC in leukaemia development. CD27 is a costimulatory receptor, leading to T-cell expansion, generation of effector function and increased cell survival. We found that CD27 signalling on LSC increases LSC proliferation and differentiation to malignant granulocytes. Since the ligand of CD27 (CD70) is solely expressed on activated lymphocytes and on mature dendritic cells, the adaptive immune response favours leukaemia progression. Therefore, blocking the CD27-CD70 interaction may be a strategy to interfere with leukaemia progression on the level of the LSC. Prof. Dr. Adrian F. Ochsenbein Universitätsklinik für medizinische Onkologie Inselspital Freiburgstrasse 10 CH-3010 Bern Phone +41 (0)31 632 84 42 Fax +41 (0)31 632 41 19 adrian.ochsenbein@insel.ch Pertz Olivier A slit/robo signaling pathway regulating contact mediated repulsion during cell migration: Implications of its deregulation for the acquisition of an invasive phenotype during breast cancer (KFS 02485-08-2009) Duration: 01.05.2010 01.05.2013 In healthy tissue, individual cells are kept in the right order through constant interaction with neighbouring cells. This process involves sampling of adjacent cells and sensing of repulsive cues that suppress cell motility. During the metastatic switch, cancer cells acquire the ability to move out and to squeeze between surrounding cell layers, finally spreading through the body and colonizing distinct organs. Thus, cell sensing may serve as an important early mechanism to impede the invasive phenotype. The aim of this project is to apply a gene inactivation approach to

identify signalling pathways that generate and/or sense repulsive signals. Understanding the molecular mechanisms underlying metastasis will be crucial for a successful cancer therapy. Prof. Dr. Olivier Pertz Institut für Biochemie und Genetik Departement Biomedizin Universität Basel Mattenstrasse 28 CH-4058 Basel Phone +41 (0)61 267 35 41 olivier.pertz@unibas.ch Petrova Tatiana Lymphatic endothelial calcineurin/ NFAT signaling in tumor lymphangiogenesis and metastasis (KLS 02570-02-2010) Duration: 01.09.2010 01.09.2013 Tumour metastasis is a major cause of cancer related mortality. Malignant cells frequently escape from the primary tumour using nearby lymphatic vessels, which normally serve to regulate body fluid balance, fat transport and immune surveillance. Understanding the process of lymphatic metastasis is thus important for developing new treatment approaches to interfere with tumour spread to distant sites. Previously we discovered that the calcineurin/nfat signalling pathway is needed for normal lymphatic vascular development. The goal of the present study is to establish the role of calcineurin/nfat in tumour lymphatic vessels and tumour cell dissemination. We plan to use genetic models in which we will inactivate calcineurin/nfat in tumour-associated lymphatic vessels and then monitor their ability to transport tumour cells to lymph nodes. In addition, we aim to identify important targets regulated by calcineurin/nfat in lymphatic endothelial cells. Identification of specific targets of calcineurin signalling is important for the development of treatment approaches targeting vascular system in diseases, such as cancer and inflammation. Prof. Dr Tatiana Petrova Centre pluridisciplinaire d oncologie (CePO) Centre hospitalier universitaire vaudois (CHUV) et Université de Lausanne Chemin des Boveresses 155 CH-1066 Epalinges Phone +41 (0)21 692 58 28 Fax +41 (0)21 692 58 72 tatiana.petrova@unil.ch Plückthun Andreas Tumor targeting of ErbB2 with designed ankyrin repeat proteins (KFS 02448-08-2009) Duration: 01.01.2010 01.01.2012 Over the last few years, we have developed a new class of alternative binding molecules, termed designed ankyrin repeat proteins (DARPins). These binders are expected to significantly improve the efficiency of tumour targeting in many types of human cancer. In contrast to conventional therapeutic antibodies, they possess outstanding biophysical properties and can be readily produced in different molecular formats, e.g. as fusion proteins with various cytotoxic moieties. Due to the many favourable attributes of DARPins, it has become possible to construct vehicles capable of inducing programmed cell death of tumour cells (apoptosis) in the absence of therapeutic payloads or other tumouricidal additives. Thus, the adverse side effects associated with unspecific toxic substances should be eliminated in the DARPin tumour therapy. Such pharmacological aspects and the overall efficacy of DARPin treatment are being presently addressed in comparative studies in animal tumour models. Prof. Dr. Andreas Plückthun Biochemisches Institut Universität Zürich Winterthurerstrasse 190 CH-8057 Zürich Phone +41 (0) 44 635 55 70 Fax +41 (0) 44 635 57 12 plueckthun@bioc.uzh.ch Pruschy Martin Differential response to proton versus photon radiotherapy: Biological implications for new indications and combined treatment concepts (KFS 02551-02-2010) Duration: 01.04.2010 01.04.2013 The most commonly used mode of radiotherapy uses an externally generated photon beam directed towards the exact delineated tumour site. But proton radiotherapy is also gaining much attention due to its improved localized delivery of radiation to the tumour site. However, there is presently a gap between the rapid introduction of proton therapy in clinical practice and the introduction of new proton treatment concepts with a lack of solid radiobiological evidence to support the expansion of new clinical indications. In collaboration with the Paul Scherrer Institute we will investigate in genetically defined tumour cells and murine tumour models the impact of specific physicochemical and molecular parameters on the relative biological effectiveness of proton radiation. We will thereby increase our general knowledge of particle interaction with tissue and the cellular stress response to proton radio therapy. The results obtained will directly influence our clinical practice of proton therapy. Prof. Dr. Martin Pruschy Labor für molekulare Radiobiologie Klinik für Radio-Onkologie UniversitätsSpital Zürich Rämistr. 100 CH-8091 Zürich Phone +41 (0)44 255 85 49 martin.pruschy@usz.ch 107

108 Radtke Freddy The role of Notch and TSLPR signaling during skin cancer (KLS 02387-02-2009) Duration: 01.08.2009 01.08.2012 Our studies previously showed that loss of Notch signalling in the skin results in a severe form of inflammation characterized as atopic dermatitis-like disease (AD, also known as eczema) due to excessive production of thymic stromal lymphopoietin (TSLP) by Notch deficient keratinocytes. TSLP is a secreted cytokine that is deeply implicated in the pathogenesis of AD and asthma in mouse and human. We genetically removed the TSLPR to prove that TSLP signalling is indeed causative of the development of AD in mice having lost Notch1 and Notch2 in the skin. These mice were rescued from developing AD; however, unexpectedly they developed rapidly growing invasive skin tumours, suggesting that TSLP induces a type of inflammation that protects pre-malignant lesions from progressing into tumours. We are currently trying to identify the cellular and molecular mechanisms of the TSLPmediated protective inflammation. This should lead to novel insights into how the immune system tries to fight against cancer. Prof. Dr Freddy Radtke UPRAD Institut suisse de recherche expérimentale sur le cancer (ISREC) Faculté des sciences de la vie EPF de Lausanne (EPFL) Station 19 CH-1015 Lausanne Phone +41 (0)21 693 07 71 freddy.radtke@epfl.ch Renner Christoph Inhibition of tumor growth by targeting cancer-associated fibroblasts (KFS 02500-08-2009) Duration: 01.01.2010 01.01.2013 Tumours are composed of tumour cells and a variable degree of stroma, which includes extra-cellular matrix and fibroblasts. These tumour fibroblasts support tumour growth and are characterized by the expression of fibroblast activation protein (FAP). FAP is a dipeptidyl peptidase known to cleave extra-cellular matrix (such as collagen), which in turn leads to enhanced metastasis formation. We postulate that FAP-blocking molecules can inhibit this process and stop tumour metastasis. Therefore, we developed mouse-human cross-reactive FAP-specific antibodies that downregulate FAP expression, and we will analyze them in mouse models for their potential to impact on metastasis formation using new imaging approaches. It is our final goal to transfer this approach into a clinical setting for the benefit of patients with advanced malignant diseases. Prof. Dr. Christoph Renner Klinik und Poliklinik für Onkologie Medizinbereich Innere Medizin Onkologie UniversitätsSpital Zürich Rämistrasse 100 CH-8091 Zürich Phone +41 (0)44 255 21 54 christoph.renner@usz.ch Ruiz i Altaba Ariel Role and prevalence of hedgehog signalling in human colorectal cancer (KFS 02359-02-2009) Duration: 01.07.2010 01.07.2013 Despite huge efforts to improve treatments, metastatic cancers are still linked to a high rate of mortality. This is the case for colon cancer, which accounts for about 10 % of all cancer deaths worldwide, with 25 % of the cases being out of any surgical therapy because of metastasis. The transition step from primary tumour to metastatic state therefore appears to be critical in the development of the disease and should be considered as a priority target for future therapies. In this imperative perspective, we propose to study, in a collaborative effort involving surgeons of the University hospital Geneva (HUG), the molecular mechanisms underlying this metastatic transition step. Our data suggest that the development of colorectal cancer requires the activity of the sonic hedgehog (SHH)-Gli pathway, a cell signalling pathway that we have previously identified as being deregulated in other cancers, namely, brain, skin and prostate cancers. From these data, (SHH)-Gli pathway should play an essential role in the tight regulation of colon cancer stem cells from which the tumour arises, as well as in later phases of the disease, like the metastatic transition. To validate these working hypotheses, we propose to compare the tumourigenic properties of colon carcinoma cells obtained from patient biopsies at different stages of the disease by using mice xenograft models. These experiments are expected to bring new insights into the molecular mechanisms underlying the biology of intestinal tumourigenesis and should allow for the identification and development of specific (SHH)-Gli pathway antagonists to treat colorectal tumours and their cancer stem cells more efficiently. Prof. Dr Ariel Ruiz i Altaba Département de génétique médicale et de développement Faculté de médecine Université de Genève 1, rue Michel-Servet CH-1211 Genève 4 Phone +41 (0)22 379 54 46 Fax +41 (0)22 379 59 62 ariel.ruizaltaba@unige.ch

Santamaria Anna Control of chromosome segregation fidelity by the Ska complex, a key regulator of stable kinetochore-microtubule attachments during mitosis (KFS 02657-08-2010) Duration: 01.02.2011 01.02.2014 During development of every organism, each dividing cell must partition its replicated genome equally into each new daughter cell. Errors in this process lead to aneuploid daughter cells with abnormal numbers of chromosomes. Aneuploidy is a remarkably common characteristic of aggressive tumours. Compelling evidence suggests that excessively stable kinetochore-microtubule (KT-MT) attachments are the root cause of chromosomal instability (CIN) in many cancer cells. Central to the machinery required for establishing stable KT-MT attachments is the Ska (for spindle and kinetochore-associated) complex. Our goal is to elucidate the role of the Ska complex in generating stable KT-MT attachments during mitosis in human cells by: 1) identifying its interaction partners and studying the regulation of the Ska complex by phosphorylation using biochemical and cell biological techniques; 2) resolve the structure of the Ska complex by X-ray crystallography; 3) analyze the abundance, stochiometry and dynamics of endogenous Ska proteins in both normal and tumour cells using mass spectrometry-based techniques. These studies should allow us to determine whether protein imbalances in key regulators of KT-MT attachments are a likely root cause of CIN in cancer cells. This will provide an opportunity to explore KT-related pathways and strategies that elevate chromosome missegregation beyond tolerable levels for therapeutic applications. Dr. Anna Santamaria Departement Biozentrum Universität Basel Klingelbergstrasse 50/70 CH-4056 Basel Phone +41 (0)61 267 18 93 Fax +41 (0)61 267 20 09 anna.santamaria@unibas.ch

110 Schär Primo DNA repair, epigenetic stability, and CpG island hypermethylation in colorectal tumorigenesis (KFS 2585-02-2010) Duration: 01.07.2010 01.07.2012 Cancer arises as a consequence of genetic mutations and epigenetic alterations in normal cells of our body. Unlike genetic mutations, epigenetic changes do not concern the DNA sequence itself but affect the patterns of heritable chemical modifications on the DNA. These are methylations of cytosine bases that act as flags to direct accurate cell type-specific gene expression. In cancer cells, these flags are often misplaced for reasons that are currently unknown. Our research has led to the discovery that a bona fide DNA repair enzyme, the thymine DNA glycosylase (TDG), does not primarily engage in the repair of DNA damage but associates specifically with gene regulatory sequences to correct errors of cytosine methylation. This newly described epigenetic function is likely to play a critical role in tumour suppression. This research project is designed to clarify if and how the loss of TDG contributes to both the development and nature of epigenetically unstable colorectal cancers. Prof. Dr. Primo Schär Institut für Biochemie und Genetik Departement Biomedizin Universität Basel Mattenstrasse 28 CH-4058 Basel Phone +41 (0)61 267 07 67 Fax +41 (0)61 267 35 66 primo.schaer@unibas.ch Schorderet Daniel Retinoblastoma: Understanding its development for better treatment (KFS 02565-02-2010) Duration: 01.08.2010 01.08.2013 Retinoblastoma is a malignant tumour of childhood affecting the developing retina due to the inactivation of both. We propose to induce apoptosis in tumoural cells by modifying molecular pathways with small peptides. Cellular and animal models will be used to study the molecular pathways involved, and new therapeutic molecules will be identified and evaluated. Availability of new therapeutic molecules will aid development of new treatments for advanced retinoblastoma stages. Prof. Dr Daniel Schorderet Institut de recherche en ophtalmologie (IRO) EPF de Lausanne et Université de Lausanne Avenue du Grand-Champsec 64 CH-1950 Sion Phone +41 (0)27 205 79 00 Fax +41 (0)27 205 79 01 daniel.schorderet@irovision.ch Swartz Melody Roles of tumor VEGF-C and CCL21 in immunological tolerance (KFS 2696-08-2010) Duration: 01.03.2011 01.03.2014 Lymph node metastasis of many cancers, including breast and skin, is the leading cause of cancer mortality. Lymph nodes that contain metastases are typically surgically removed, and tumour-associated lymphatic vessels have mainly been considered as routes for tumour dissemination. We have hypothesized that tumours can use lymphatic vessels and drainage to lymph nodes to reprogram the immune system, promoting immunological tolerance, where tumour cells are considered normal by the immune system. This research project will explore this new hypothesis and test its validity in skin cancer models in mice. Specifically, we will determine how tumour-associated lymphatics and their drainage to the lymph node affects host immunity to the tumour and explore strategies to reverse this immunological tolerance. We believe that this research will introduce a new paradigm in our understanding of how tumours modulate the host immune system, leading to new immunotherapeutic strategies targeting lymphatic vessels and tumour-draining lymph nodes for breaking this tolerance and driving efficient anti-tumour immune responses. Prof. Dr. Melody Swartz Institute of Bioengineering and Institute for Experimental Cancer Research EPF de Lausanne (EPFL) Station 15 CH-1015 Lausanne Phone +41 (0)21 693 96 86 melody.swartz@epfl.ch Thoma Nicolas The molecular basis of the defense against skin cancer: Structural studies of the DDB1- DDB2-XPC/Rad23 UV-damage handover complex (OCS 02365-02-2009) Duration: 01.09.2009 01.09.2011 Genetic instability is a hallmark of all cancer cells. The loss of genetic information functions as initiator in the formation of the tumour cells, as well as in driving the malignant transformation process. Persistent UV irradiation of exposed skin cells leads to an accumulation of a number DNA lesions. If left unrepaired, this DNA damage facilitates formation of skin tumours ranging from malignant melanomas, squamous cell carcinomas to basal cell carcinomas. The proposal focuses on the DDB1-DDB2 protein complex and its interactions with the XPC-Rad23 complex. Together these complexes recognize DNA damage and initiate the repair response. We aim to use a combination of X-ray crystallography and biochemical techniques to understand how these crucial protein complexes detect and repair DNA damage and thus serve as a safeguard against skin cancer. Dr. Nicolas Thoma Friedrich Miescher Institut für biomedizinische Forschung (FMI) Maulbeerstrasse 66 CH-4058 Basel Phone +41 (0)61 697 86 30 nicolas.thoma@fmi.ch

Thome-Miazza Margot Analysis of the role of the protease MALT1 in human lymphomas (KFS 02561-02-2010) Duration: 01.08.2010 01.08.2013 The activation and subsequent proliferation of lymphocytes is normally initiated by the detection of the presence of an infection. This process is perturbed in lymphomas or leukaemia, a form of cancer characterized by uncontrolled lymphocyte proliferation. Our goal is to clarify the relevance of the protease MALT1 in this process, since MALT1 plays an important role in the proliferation of lymphocytes. By comparing resting and activated lymphocytes, we could show that MALT1 is only active in activated lymphocytes. Through systematic comparison of cell lines derived from diffuse large B-cell lymphomas (DLBCL), we then showed that MALT1 is hyperactive in a subset of this type of lymphoma, called the ABC subtype of DLBCL. Moreover, treatment of cells derived from this lymphoma type with a MALT1 inhibitor led to inhibition of the growth of the cells in vitro. The goal of our ongoing studies is to find out whether the activity of MALT1 is also relevant for other types of lymphomas, such as cutaneous T-cell lymphomas or lymphomas induced by the oncogenic human herpesvirus-8 (HHV-8). We hope that these studies of the relevance of MALT1 for different lymphoma types will contribute to the development of novel strategies for the diagnosis and therapy of this form of cancer. Prof. Dr Margot Thome-Miazza Département de biochimie Université de Lausanne 155, chemin des Boveresses CH-1066 Epalinges Phone +41 (0)21 692 57 37 Fax +41 (0)21 692 57 05 margot.thomemiazza@ib.unil.ch Tschan Mario P. The importance of autophagy in normal and leukemic myelopoiesis (KFS 02486-08-2009) Duration: 01.02.2010 01.02.2012 Autophagy, literally self-eating, is a mechanism involved in the degradation of organelles or protein aggregates. Its role in cancer is controversial: First, autophagy contributes to genome stability of healthy cells; second, it promotes tumour cell survival upon anti-cancer therapy. This study aims at elucidating the function of autophagy in the pathogenesis of acute promyelocytic leukaemia (APL). Using an RNA interference-based reverse genetics screen, we found that inhibiting autophagy impairs neutrophil differentiation of APL cells. Characterizing the autophagic molecular pathways involved in neutrophil development may lead to novel strategies to treat APL. One might imagine combining current APL differentiation therapy with autophagy-inducing drugs. PD Dr. Mario P. Tschan Medizinische Onkologie/Hämatologie Departement für klinische Forschung Universität Bern MEM E829 Murtenstrasse 35 CH-3010 Bern Phone +41 (0)31 632 87 80 mtschan@dkf.unibe.ch Weller Michael Angiogenesis and invasion in glioblastoma: The therapeutic options and risks of co-targeting VEGF and TGF-beta (KFS 02694-08-2010) Duration: 01.02.2011 01.02.2014 Glioblastoma, the most common intrinsic brain tumour, has a very poor prognosis. At present, clinical research in glioma therapy is focusing strongly on novel agents targeting angiogenesis, mostly antagonists of vascular endothelial growth factor (VEGF) signalling. However, there is increasing evidence that the inhibition of angiogenesis alone is insufficient to control glioma growth for more than a few months and that gliomas may develop dangerous escape strategies including a more invasive phenotype in response to antiangiogenic therapy. This research project will address the hypothesis that the switch to invasiveness triggered by antiangiogenic agents depends critically on the biological effects of the cytokine transforming growth factor beta (TGF-beta). Here, we will try to dissect the complex interactions between the VEGF and TGF-beta signalling pathways in glioblastoma. Our aim is to optimize antiangiogenic therapies against glioblastomas. To achieve this, we perform a preclinical study using standard approaches for in vitro and in vivo analysis. In the long term we aim to develop new strategies for clinical trials for the benefit of patients. Prof. Dr. Michael Weller Klinik für Neurologie UniversitätsSpital Zürich Frauenklinikstrasse 26 CH-8091 Zürich Phone +41 (0)44 255 55 00 Fax +41 (0)44 255 45 07 michael.weller@usz.ch Widmann Christian The 317-326 sequence of RasGAP as potential anti-metastatic agent (KFS 02543-02-2010) Dissemination of cancer cells in the organism from primary tumours is the event most dreaded by oncologists. Indeed, metastasis formation is the primary cause of death resulting from cancer. In our laboratory, we have discovered that a peptide derived from the RasGAP protein increases in vitro the adherence of cancer cells and inhibits their migratory capacity. This peptide therefore has an anti-metastatic potential. 111

112 In this project we will investigate whether the RasGAP peptide can indeed block the formation of metastases in mice. We will also study the mode of action of the peptide on tumour cells by investigating the effect of the peptide on cell adhesion molecules and on the cytoskeleton. These experiments might lead to clinical application in humans. Prof. Dr Christian Widmann Département de physiologie Université de Lausanne Rue du Bugnon 7 CH-1005 Lausanne Phone +41 (0)21 692 51 23 Fax +41 (0)21 692 55 95 christian.widmann@unil.ch Wymann Matthias Paul Identification and modulation of targets to reprogram glioblastoma cancer stem cells (KFS 02680-08-2010) Duration: 01.01.2011 01.01.2014 Glioblastoma multiforme (GBM) is a very aggressive brain tumour. A signalling pathway connecting a lipid kinase (phosphoinositide 3-kinase (PI3K)) to a nutrient sensor complex (target of rapamycin (mtor)) constitutes a central piece of GBM aetiology. To date, little is known regarding relevant signalling downstream of the lipid product PtdIns(3,4,5)P3 of PI3Ks. Exploring structural determinants of putative phosphoinositide-interacting proteins, we will assemble pathway modules to be targeted in GBM. We have developed enrichment protocols for GBM-derived cancer stem cells (GBM CSCs). These will be monitored for phenotypic outputs of pharmacologically and genetically modulated PIiPs-dependent pathways. Pilot studies indicate that reprogramming GBM CSCs could drive them towards differentiation and cell death. The identification of novel signalling elements in GBM CSCs is of critical importance for developing novel strategies for the treatment of this devastating disease. Prof. Dr. Matthias Paul Wymann Institut für Biochemie und Genetik Departement Biomedizin Universität Basel Mattenstrasse 28 CH-4058 Basel Phone +41 (0)61 695 30 46 matthias.wymann@unibas.ch Zaugg Kathrin Elucidating the role of the hypoxiaprotective gene CPT1C (Carnitine Palmitoyl-transferase 1C) in carcinogenesis (KLS 02569-02-2010) Duration: 01.05.2010 01.05.2011 Hypoxia is a key regulator in tumour growth and can lead through an epigenetic phenomenon to more resistant cancer cells. In our laboratory we are investigating the mechanism of a gene that modulates cancer cell death under hypoxic conditions. In addition, it promotes migration and invasion when overexpressed. Dr. Kathrin Zaugg Labor für angewandte Radio-Onkologie UniversitätsSpital Zürich NUK E 17 Rämistrasse 100 CH-8091 Zürich Phone +41 (0)44 255 29 30 Fax +41 (0)44 255 44 35 kathrin.zaugg@usz.ch Zavolan Mihaela Identification of cancer-related targets of individual members of the mir-17~92 cluster of mirna (KFS 02477-08-2009) Duration: 01.01.2010 01.01.2013 MicroRNAs (mirnas) are short RNA molecules that regulate expression of protein-coding genes that play important roles in the growth, division, differentiation and apoptosis of cells. Some act as cancer suppressors, downregulating cancer-promoting cellular factors, while others are oncogenic, promoting malignancies. We are studying the mir- 17~92 mirna family, which consists of six related mirnas that collectively have been implicated in various lymphomas, as well as lung, bladder and colon cancers. Our project aims to uncover the targets and pathways that individual members of the mir-17~92 cluster affect in bringing about carcinogenesis. We combine high-throughput experiments with computational predictions and direct molecular biology techniques for target validation. By observing the behaviour of tumour-derived cells in which we deplete these targets with small interfering RNAs, we will further identify the role of these targets in tumour formation. The targets that we hope to identify would constitute potential factors for novel drugs that prevent or slow down cancer formation. Prof. Dr. Mihaela Zavolan Departement Biozentrum Universität Basel Klingelbergstrasse 50 70 CH-4056 Basel Phone +41 (0)61 267 15 77 mihaela.zavolan@unibas.ch

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Clinical research 115 Challenges for clinical cancer research in Switzerland The aim of patient-centred clinical cancer research is to develop new cancer therapies and to optimize existing tumour therapies so as to improve the prognosis and tolerability of treatment in patients with cancer. Typical research questions are, for example: Will a combination of different chemotherapy drugs produce better results? Will this cause more side effects? What is the optimal combination of the three types of treatment chemotherapy, radiation therapy, and surgery for certain types of cancer and patient groups? As chemotherapy is often very expensive, an increasing number of investigations are also examining the cost and benefits of treatments. For patients with cancer, clinical cancer research has two benefits: For one, participation in clinical trials gives the patient early access to new treatments. For another, treatment quality is the highest at institutions that conduct clinical studies, as a recent study on breast cancer treatment in Switzerland showed [1]. Since also medium-sized and large hospitals are frequently not able to conduct a research project by themselves, clinical cancer research in Switzerland depends upon good networking of the research groups and centres. For many years now, this task has been taken on by the Swiss Group for Clinical Cancer Research (SAKK) for adults and by the Swiss Paediatric Oncology Group (SPOG) for children. The activities of the two non-profit organizations are funded for the most part by research grants from the Swiss government (State Secretariat for Education Prof. Beat Thürlimann, MD Head of the Breast Centre at the Cantonal Hospital of St Gallen and president of the Swiss Group for Clinical Cancer Research (SAKK) Arnoud Templeton, MD Senior physician at the Cantonal Hospital of St Gallen and medical advisor of the Swiss Group for Clinical Cancer Research (SAKK)

116 In addition to study protocol and patient information, the complete proposal for a clinical trial also contains information documenting the necessary qualifications of the physicians involved. The proposal is sent first to the responsible cantonal ethics committees, which may request a revised version prior to approval or rejection. The ethics committees carefully examine the study s compliance with national and international ethical guidelines and conformance with the guideline for Good Clinical Practice (GCP) [2]. If the ethics committees approve a study, the documents are then submitted to Swissmedic, the Swiss Agency for Therapeutic Products, which either approves the proposal within 30 days or sends it back for revision. Once Swissmedic has given approval, the clinical trial can be conducted and evaluated in accordance with the study protocol. Difficulties in clinical research In many Swiss hospitals, knowledge of the eminent importance of clinical research has grown in past years. However, it is a great challenge for a hospital to provide in addition to its routine operation the human and financial resources required for a clinical trial. Many researchers, doctors, and patients have complained about the increasing bureaucratization of research in recent years. The administrative and financial expense is absolutely prohibitive for small studies with only a small number of patients (for example in paediatrics or rare diseases), with the result that these kinds of studies are increasingly no longer being conducted. It is also problematic when reviewing proposals for research projects that use alreadyregistered drugs, the authorities apply the same strict criteria as they do for new or less well-known drugs. This occasionally leads to requirements that are hardly comprehensible, and it ultimately slows progress in cancer treatment. Less detailed regulaand Research). Other financial sponsors are companies, the Foundation Cancer Research Switzerland, the Swiss Cancer League, santésuisse (the association of Swiss health insurers), and private foundations like the Swiss Foundation for Clinical Cancer Research. Even though clinical cancer research in Switzerland receives international attention and the findings have an influence on everyday clinical practice, benefitting patients directly, there is always the question as to how clinical research can be improved, how existing resources can be utilized even better and benefit more patients. Approval process for a clinical study A clinical research project or study usually begins with an idea or a specific question formulated by a research group or a trial investigator, the study leader. First, the study design is worked out, defining the hypothesis and how the hypothesis will be tested and establishing the number of patient participants that will be required. This number provides a first clue as to whether a study can be conducted at all or whether international cooperation is appropriate. The actual study plan, the protocol, is usually written in cooperation with the organization that will conduct the study. For many cancer-related studies in Switzerland, this organization is the SAKK. The SAKK funds the study, secures the insurance coverage, and has the main responsibility for the quality of the study data. The protocol is a document outlining the background and reason, the objectives, and the exact procedure for performing the study, and it describes the conditions under which the study will be conducted and monitored.

tory requirements would also be desirable for therapies that in addition to chemotherapy also include surgery and/or radiation therapy, or for projects such as quality of life research and studies on health economics (for example, requirements in the areas of bookkeeping, safety reporting, reporting of insignificant protocol changes) [3]. To make the best possible use of the existing leeway in the regulations, all parties involved (study leader, organization conducting the trial, ethics committee, Swissmedic) need more training, experience, mutual trust, and a good eye for realistic risk assessment. Through this, for instance, unnecessary duplication such as the review of one and the same study by multiple ethics committees could be avoided. In addition, clear designation of responsibilities is important: For instance, Swissmedic could recognize the decisions by ethics committees or by the Federal Data Protection and Information Commissioner (FDPIC), without having to evaluate these aspects of the study proposals all over again. These are certainly ways to increase the efficiency of research and improve utilization of the available resources without any loss of quality [3]. Some studies even showed that duplicative reviews and in part contradictory decisions worsen the quality of research rather than improve it [4]. should rather lay down the fundamental principles of the GCP. It would also seem appropriate to exempt clinical trials using already approved medicines from the requirement to obtain approval by Swissmedic as well as to provide a simplified approval process for international studies that have already been approved by responsible foreign authorities. In countries having comparable regulatory and legal standards (such as EU countries, the United States, and Canada), the research topic and the ethical context are reviewed in an analogous manner as they are in Switzerland before a clinical trial is approved. For that reason, yet another scientific review by the Swiss authorities is unnecessary. What should be reviewed in Switzerland would then be only the national and local conditions, such as the qualifications of the study leader and the competency of the centre. Unquestionably, all clinical trials should be recorded in study registries that are accessible to the public. This improves the coordination of research efforts and also makes it difficult for those conducting the study to conceal unwanted findings. This should include recording the studies in international study registry databases that are already being run successfully, as the SAKK and its cooperation partners in national and international patient-centred cancer research have done for years. 117 Issues concerning the new Swiss law on research involving humans Elaboration of the law on research involving humans (Humanforschungsgesetz, HFG) is very important for the future of clinical research. Fortunately, some of the suggestions mentioned above were already discussed in the first parliamentary deliberations on the HFG. Many research institutions agree that the law should not strictly adhere to the GCP guideline word-for-word in all areas of clinical research but Cost coverage for standard medical procedures in studies One problem in clinical research that should be better regulated by law is cost coverage by the health insurer for the study patients routine diagnostics and routine treatments. The medical treatment and care costs in patient-centred clinical studies should be as in other industrialized countries covered by the health insurance companies [5, 6]. Without this prerequisite, clinical research in Switzerland would

118 be totally unaffordable for academic organizations and institutions, and, in the end, unfeasible. In addition to elaborating the HFG, solving this cost coverage problem through a revision of the Swiss health insurance law (Krankenversicherungsgesetz, KVG, Art. 49) is an urgent concern. Institutions like SAKK or the six competence centres for clinical research (Clinical Trial Units, CTUs) in Swiss hospitals can also conduct successful research within the current regulatory conditions. But this is only possible with clearly higher costs and human resources. If the right course is set through the legislation, Swiss research can become more attractive in international comparison, the quality of patient care and access to new medications can be improved, and support of the young generation of physicians and researchers can be optimized. Implementation of the suggestions offered above would contribute towards ensuring that Swiss research remains innovative and of the highest quality to the benefit of all persons affected by cancer. Prof. Beat Thürlimann, MD Beat Thürlimann is head physician and head of the Breast Centre at the Cantonal Hospital of St Gallen. After completing his medical studies at the University of Zurich and working as an assistant physician at University Hospital Zurich, he worked at Pretoria Academic Hospital in South Africa and then at the Cantonal Hospital St Gallen. He has been an active member of the SAKK board for many years and was appointed president in July 2010. He served as president of the breast cancer project group from 1993 to 2005. His main professional interests are breast cancer, adjuvant therapy, new medications, international research and gynaecological tumours. Phone +41 (0)71 494 18 88 beat.thuerlimann@sakk.ch www.brustzentrum-sg.ch Arnoud Templeton, MD Arnoud Templeton works as medical advisor at the SAKK Coordinating Centre in Bern. He has been a senior clinical and research fellow in oncology and haematology at the Cantonal Hospital of St Gallen since April 2011. His main clinical and research interests are urogenital tumours and integrative oncology. Phone +41 (0)71 494 10 62 arnoud.templeton@sakk.ch www.onkologie-sg.ch

References 119 1. Ess S, Joerger M, Frick H, Probst-Hensch N, Vlastos G, Rageth C, Lütolf U, Savidan A, Thürlimann B. Predictors of state-of-the-art management of early breast cancer in Switzerland. Ann Oncol 2011;22(3):618-624. 2. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Guideline for Good Clinical Practice E6 (R1). http://www.ich.org/fileadmin/public_web_site/ ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_ R1 Guideline.pdf 3. Stewart DJ, Whitney SN, Kurzrock R. Equipoise lost: ethics, costs, and the regulation of cancer clinical research. J Clin Oncol 2010;28:2925-2935. 4. Menikoff J. The paradoxical problem with multiple-irb review. N Engl J Med 2010;363(17):1591-1593. 5. U.S. Department of Health & Human Services (DHHS). Medicare Clinical Trial Policy. http://www.cms.gov/ transmittals/downloads/r74ncd.pdf 6. Department of Health, United Kingdom (UK). Attributing revenue costs of externally-funded non-commercial research in the NHS. (ARCO)http://www.dh.gov.uk/ prod_consum_dh/groups/dh_digitalassets/@dh/@en/ documents/digitalasset/dh_4125282.pdf

Clinical research List of completed research projects from July 2008 to December 2010 Aebersold Daniel M. OCS 01681-02-2005 CHF 172,800. Klinik und Poliklinik für Radio-Onkologie, Inselspital, Bern The role of activating point mutations in the met receptor tyrosine kinase in tumor radioresistance Baege Astrid KLS 02220-02-2008 CHF 220,100. Klinik für Gynäkologie, UniversitätsSpital Zürich, Zürich The role of adult stem cells in HPV-associated carcinogenesis: Identification of the HPV target cell capable of driving viral persistence 120 Ballmer Peter E. OCS 02000-02-2007 CHF 155,800. Klinik für Innere Medizin, Departement für Medizin, Kantonsspital Winterthur, Winterthur Influence of a nutritional intervention on clinical course and quality of life in cancer patients Benhattar Jean OCS 01638-02-2005 CHF 203,000. Institut universitaire de pathologie de Lausanne (IUP), Centre hospitalier universitaire vaudois (CHUV), Lausanne Identification of biomarkers for early cancer detection in Barrett s esophagus patients using methylation profiles and the Wnt pathway Bertoni Francesco KLS 01835-02-2006 CHF 177,900. Gruppo genomica funzionale e linfomi, Laboratorio di oncologia sperimentale, Istituto oncologico della Svizzera italiana (IOSI), Bellinzona Evaluation of the tyrosine kinase SYK as a possible therapeutic target in lymphomas Bertoni Francesco OCS 01939-08-2006 CHF 226,800. Gruppo genomica funzionale e linfomi, Laboratorio di oncologia sperimentale, Istituto oncologico della Svizzera italiana (IOSI), Bellinzona Genome-wide DNA profiling as outcome predictor in diffuse large B-cell lymphoma Bertoni Francesco OCS 02034-02-2007 CHF 157,800. Gruppo genomica funzionale e linfomi, Laboratorio di oncologia sperimentale, Istituto oncologico della Svizzera italiana (IOSI), Bellinzona Extranodal, nodal and splenic marginal zone B-cell lymphomas: How much are they related to each other? Bohlius Julia OCS 02146-10-2007 CHF 128,100. Forschungsgruppe Krebs, Institut für Sozial- und Präventivmedizin (ISPM), Universität Bern, Bern Individual patient data meta-analysis on the effects of erythropoiesis-stimulating agents in cancer patients Bourquin Jean-Pierre KLS 02124-08-2007 CHF 226,600. Abteilung Onkologie, Kinderspital Zürich, Universitäts-Kinderkliniken, Zürich A leukemia xenotransplantation model to evaluate combinatorial approaches for the treatment of de novo drug resistant childhood acute lymphoblastic leukemia Continuation in the project: Bourquin Jean-Pierre KFS 02453-08-2009 CHF 125,500. Abteilung Onkologie, Kinderspital Zürich, Universitäts-Kinderkliniken, Zürich Pre-clinical evaluation of a new pharmacological approach using obatoclax for chemosensitization of drug resistant childhood acute lymphoblastic leukemia Duration: 01.03.2010 01.03.2011 Carbone Giuseppina OCS 01913-08-2006 CHF 183,800. Laboratorio di oncologia sperimentale, Istituto oncologico della Svizzera italiana (IOSI), Bellinzona Functional and clinical implications of deregulated expression of ETS transcription factors in prostate cancer Cozzi Luca OCS 01821-02-2006 CHF 80,800. Servizio di fisica medica, Istituto oncologico della Svizzera italiana (IOSI), Ospedale regionale di Bellinzona e valli, Bellinzona Heterogeneity management in advanced algorithms for photon dose calculation and the clinical impact on breast and lung cancer radiotherapy. Validation of existing models against experimental studies, Monte Carlo simulations and determination of potential

De Libero Gennaro KLS 02211-02-2008 CHF 159,500. Experimentelle Immunologie, Departement Biomedizin, Universität Basel, Basel Lipid-specific T-cells against leukaemic blasts Dirnhofer Stephan OCS 01792-10-2005 CHF 297,800. Institut für Pathologie, Universitätsspital Basel, Basel Inducing cell death in apoptosis-resistant hematological tumors: Impact on diagnosis and therapeutic intervention Doucey Marie-Agnès OCS 02069-04-2007 CHF 214,800. Centre pluridisciplinaire d oncologie (CePO), Centre hospitalier universitaire vaudois (CHUV), Lausanne Functional and biochemical characterization of human monocyte-like circulating cells in breast cancer patients: Relevance to tumor growth and angiogenesis Dubey Raghvendra K. OCS 01551-08-2004 CHF 258,300. Klinik für Reproduktions-Endokrinologie, UniversitätsSpital Zürich, Zürich Pathophysiological role of estrogen metabolism in breast cancer 121 Frattini Milo OCS 01921-08-2006 CHF 102,300. Laboratorio di diagnostica molecolare, Istituto cantonale di patologia (ICP), Locarno Characterization of EGFR deregulation and EGFR downstream cascade in colorectal cancer patients, and relationship to new targeted therapies Garayoa Elisa Garcia KLS 02040-02-2007 CHF 150,700. Zentrum für radiopharmazeutische Wissenschaften, Paul Scherrer Institut (PSI), Villigen Development of new bombesin-based radiopharmaceuticals with improved pharmacokinetics as potential imaging and therapeutic agents for bombesin receptor-positive tumours Gautschi Oliver KLS 02164-02-2008 CHF 218,200. Departement für klinische Forschung, Universität Bern, Inselspital, Bern Regulation of ld1 expression by Src in cancer: Clinical implications Heim Markus Hermann OCS 02192-02-2008 CHF 245,200. Klinik für Gastroenterologie und Hepatologie, Universitätsspital Basel, Basel Hepatocarcinogenesis in chronic hepatitis C Continuation of the project: Heim Markus Hermann KLS 01832-02-2006 CHF 231,700. Klinik für Gastroenterologie und Hepatologie, Universitätsspital Basel, Basel Hepatocarcinogenesis in chronic hepatitis C Heinzelmann-Schwarz Viola OCS 02115-08-2007 CHF 232,100. Translational Research Group, Klinik für Gynäkologie, Medizinbereich Frau-Kind, UniversitätsSpital Zürich Detection of anti-glycan autoantibodies as biomarkers of high stage serous ovarian cancer; acronym: GOS-study Herrmann Richard KLS 02067-04-2007 CHF 490,000. Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK), Koordinationszentrum, Bern The SAKK initiative for regional hospitals Hess Christoph OCS 02266-08-2008 CHF 103,700. Ambulante Innere Medizin, Medizinische Poliklinik, Universitätsspital Basel, Basel Innate immunity, cytokine polymorphisms, and development of post-transplant lymphoproliferative disease in kidney transplant recipients Hess Viviane KLS 01881-04-2006 CHF 87,800. Medizinische Onkologie, Universitätsspital Basel, Basel Improving treatment for patients with advanced pancreatic cancer (APC): A Swiss-wide effort Hoek Keith OCS 01927-08-2006 CHF 145,500. Dermatologische Klinik, Medizinbereich Trauma-Derma-Rheuma-Plastische Chirurgie, UniversitätsSpital Zürich, Zürich Clinical implications of Wnt signal-driven regulation of melanoma metastatic potential

Hunger Robert E. OCS 02262-08-2008 CHF 91,500. Universitätsklinik für Dermatologie, Inselspital, Bern Malignant melanoma: Correlation of dendritic cell (DC) and T-cell markers with prognosis Imhof Beat A. OCS 01653-02-2005 CHF 177,600. Département de pathologie et immunologie, Faculté de médecine, Centre médical universitaire (CMU), Université de Genève, Genève The mechanism of anti-jam-c antibodies blocking tumor angiogenesis Irminger-Finger Irmgard KLS 01962-10-2006 CHF 204,000. Laboratoire de gynécologie-obstétrique moléculaire, Département de gynécologie et d obstétrique, Maternité, Hôpitaux universitaires de Genève (HUG), Genève BRCA1-associated protein, BARD1, a molecular target for breast cancer screening and cancer therapy 122 Kalberer Christian P. OCS 01870-02-2006 CHF 155,000. Labormedizin, Diagnostische Hämatologie, Universitätspital Basel, Basel Role of NKG2D receptor-ligand interactions in the recognition of human B-cell neoplasms by natural killer cells Kalia Yogeshvar N. OCS 01753-08-2005 CHF 168,600. Section des sciences pharmaceutiques (Ecole de pharmacie Genève Lausanne), Université de Genève, Genève Non-invasive transdermal iontophoretic delivery of antiemetic drugs for the treatment of chemotherapyinduced nausea and vomiting Maiwald-Urosevic Mirjana OCS 01934-08-2006 CHF 237,200. Dermatologische Klinik, Medizinbereich Trauma-Derma-Rheuma-Plastische Chirurgie, UniversitätsSpital Zürich, Zürich Role of versican in the biology of Sézary cells Matthes Thomas OCS 01781-08-2005 CHF 201,900. Service d hématologie, Département de médecine interne, Hôpitaux universitaires de Genève (HUG), Genève Analysis of transcription factors PU.1 and GATA-1 functions in myelodysplastic syndromes, in acute myeloid leukemia and in leukemia stem cells Müller Beatrice U. OCS 01731-08-2005 CHF 249,000. Departement für allgemeine Innere Medizin und klinische Forschung, Inselspital, Bern The master transcription factor PU.1 is essential for normal hematopoiesis: Analysis of PU.1 alterations in patients with acute myeloid leukemia (AML) Perrier Patrick OCS 01911-08-2006 CHF 150,000. Service de dermatologie, Département de médecine, Centre hospitalier universitaire vaudois (CHUV), Lausanne Impact of UV light on melanoma development Renevey Philippe OCS 01777-08-2005 CHF 188,600. Centre suisse d électronique et de microtechnique (CSEM), Neuchâtel Development of a voice restoration system for laryngectomees in order to improve their social interaction Schäfer Beat W. OCS 02264-08-2008 CHF 200,600. Abteilung Onkologie, Kinderspital Zürich, Universitäts-Kinderkliniken, Zürich Oncogenic fusion proteins as therapeutic targets in pediatric sarcomas Continuation of the project: Schäfer Beat W. OCS 01944-08-2006 CHF 173,200. Abteilung Onkologie, Kinderspital Zürich, Universitäts-Kinderkliniken, Zürich Prognostic classification of rhabdomyosarcoma: A combined retro- and prospective study Speiser Daniel E. OCS 01917-08-2006 CHF 211,500. Ludwig Institut für Krebsforschung, Universitätsspital Lausanne, Lausanne Analysis of key mechanisms of human melanoma specific CD8 + T-cell responses: Long term persisting clonotypes and strong effector functions Stahel Rolf A. OCS 01915-08-2006 CHF 148,800. Klinik und Poliklinik für Onkologie, Medizinbereich Innere Medizin-Onkologie, UniversitätsSpital Zürich, Zürich SAKK trial 17/04 on neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma (MPM) with or without hemithoracic radiotherapy, including translational research

Taverna Christian OCS 02125-08-2007 CHF 223,700. Onkologie, Kantonsspital Münsterlingen, Münsterlingen Comparing two schedules of rituximab maintenance in rituximab-responding patients with untreated, chemotherapy resistant or relapsed follicular lymphoma: A randomized phase III trial of the SAKK (Swiss Group for Clinical Cancer Research) Terracciano Luigi M. OCS 02005-02-2007 CHF 208,600. Abteilung für Molekularpathologie, Institut für Pathologie, Universität Basel, Basel HOX A13 hyper-expression in liver cancer: A potential node toward angiogenesis Thalmann George N. OCS 01752-08-2005 CHF 190,300. Klinik und Poliklinik für Urologie, Inselspital, Bern Impact of therapeutic and preventive strategies in prostate cancer on prostate-specific antigen (PSA), gene expression and tumor cell survival Theurillat Jean-Philippe KLS 02014-02-2007 CHF 173,300. Institut für klinische Pathologie, UniversitätsSpital Zürich, Zürich Synthetic lethality in the context of autophagy-deficiency 123 Timmermann Beate OCS 01694-04-2005 CHF 113,300. Westdeutsches Protonentherapiezentrum Essen (WPE), Universitätsklinikum Essen, Essen, Deutschland Prospective evaluation of late effects and quality of life in childhood cancer after spot-scanning proton therapy at the Paul Scherrer Institute von der Weid Nicolas KLS 01605-10-2004 CHF 265,900. Service de pédiatrie, Centre hospitalier universitaire vaudois (CHUV), Lausanne Long-term outcome of childhood cancer: Incidence and spectrum of late effects Wodnar-Filipowicz Aleksandra OCS 02175-02-2008 CHF 162,000. Basel Stem Cell Center of Competence, Medizinische Fakultät, Universität Basel, Basel Immunotherapy of human leukemia with natural killer cells: From bench to bedside Continuation of the project: Wodnar-Filipowicz Aleksandra OCS 01664-02-2005 CHF 301,500. Basel Stem Cell Center of Competence, Medizinische Fakultät, Universität Basel, Basel Role of the natural killer cell receptors NCR and KIR in immune defence against human leukemia Zaman Khalil OCS 02029-02-2007 CHF 54,200. Centre pluridisciplinaire d oncologie (CePO), Centre hospitalier universitaire vaudois (CHUV), Lausanne Monitoring of angiogenesis-related molecules during first line chemotherapy with bevacizumab (Avastin) and pegylated liposomal doxorubicin (Caelyx) for advanced stage breast cancer: A substudy of the SAKK 24/06 trial Zhong Xiao Yan OCS 01993-02-2007 CHF 173,600. Forschungsgruppe pränatale Medizin und gynäkologische Onkologie, Departement Biomedizin, Universität Basel, Basel Investigating tumour-derived methylation DNA in circulation as markers for non-invasive screening, early diagnosis, monitoring and determination of the prognosis of breast cancer Zucca Emanuele OCS 01709-04-2005 CHF 111,600. Istituto oncologico della Svizzera italiana (IOSI), Ospedale San Giovanni, Bellinzona A prospective clinico-pathologic study of primary mediastinal B-cell lymphoma (PMBCL)

Clinical research Presentation of completed research projects from July 2008 to December 2010 124 Aebersold Daniel M. The role of activating point mutations in the met receptor tyrosine kinase in tumor radioresistance (OCS 1681-02-2005) The growth factor receptor Met activates various pathways and corresponding biological functions that are implicated in the development of malignant tumours, including critical roles in tumour progression and metastasis. Moreover, it was demonstrated that the activation of this receptor can adversely affect the response of malignant tumour cells to chemotherapy and radiotherapy. Consequently, Met is considered to be a promising molecular target for the development of new cancer drugs. Various mechanisms that can lead to excessive activation of the Met receptor in tumours have been described. In this regard, Met receptor overexpression and the occurrence of activating point mutations are the most prevalent. The aim of this research project was to investigate in more detail the importance of activating Met mutations, from both the biological and clinical point of view. For this purpose, the following sub-projects were pursued: 1) The clinical study focused on the potential role of the MET variant Y1253D, for which we previously suggested a role in tumour response to radiation therapy, in metastatic head and neck squamous cells carcinoma. This work performed on biopsy samples from a prospective randomised trial combining radiotherapy and chemotherapy confirmed a role for an activating MET mutation in metastasis of these tumours. 2) The scope of this sub-study was to perform a characterization of the response of four MET mutated variants, all of clinical significance, to the small molecule inhibitor SU11274 before a combination treatment with IR could be performed. The data obtained suggest that although all four mutants are responsive to SU11274, considerable differences in IC50 were observed on various MET-dependent biochemical and biological endpoints. Those response differences would have to be taken into consideration once SU11274 is combined with IR. 3) This study focused on mechanistic aspects that underlie the molecular cross-talk between MET and the DNA damage response in cells harbouring both overexpression of MET and MET mutations. The work shows that MET inhibition results in reduced clonogenic survival of cells to IR, which is accompanied by increased apoptosis. The work also shows that MET inhibition cooperates with DNA damaging agents to induce double strand DNA breaks (DSBs) in a synergistic manner, and one of the reasons for this synergism is the fact the MET inhibition alone results in high levels of DSBs. The study also shows that Met inhibition results in blocking of a major checkpoint signalling pathway, the ATR-CHK1-CDC25, which results in disruption of a post-damage S-phase associated cell cycle arrest, which could eventually lead to mitotic entry of cells that harbour high levels of unrepaired DSBs. 4) In this study we further explored previous findings, published in 2008, coupling MET to effectors of DSBs repair via homologous recombination. In that respect, by using the DR-GFP homologous recombination (HR) assay, we show that MET inhibition results in attenuation of HR in a dose-dependent manner in cells harbouring MET overexpression and MET mutants. Moreover, mechanistically the study shows that this MET-dependent inhibition of HR is coupled to a reduction of nuclear RAD51 and a disruption of the physical association between RAD51 and BRCA2, which is crucial for successful HR. The overall objective of the research project was to pave the way for the implementation of genetic and mechanistic evidence related to the growth factor receptor Met in clinical research protocols to test the combination of Met inhibition with conventional radiotherapy or chemotherapy. Prof. Dr. Daniel M. Aebersold Universitätsklinik für Radio-Onkologie Inselspital/Universität Bern Freiburgstrasse CH-3010 Bern Phone +41 (0)31 632 24 31 Fax +41 (0)31 382 23 42 daniel.aebersold@insel.ch Baege Astrid The role of adult stem cells in HPVassociated carcinogenesis: Identification of the HPV target cell capable of driving viral persistence (KLS 02220-02-2008) Objective Cervical cancer is still the second most common malignancy-related cause of death worldwide. Persistent infection with high risk human papillomavirus (HPV) is necessary for the emergence of cervical cancer, but the crucial factors determining persistence are largely unknown. The overall goal is to identify stem cells within the human cervical epithelium to further investigate their role during HPV-transmission, establishment of persistent infection and HPV-induced transformation. Methods Epithelial cells are isolated from fresh human cervical tissue and fractionated by FACS sorting. Subpopulations of putative stem cells, transit amplifying cells and differentiating cells are sequentially subjected to microarray analysis to compare gene expression pattern. Recruited stem cell markers will be used to localize stem cells within the cervical epithelium. Advanced organotypic cervical explant models will be infected with fluorescent high risk HPV pseudoviruses, and the course of infection will be monitored to identify the HPV target cell capable of maintaining the viral DNA over a course of time.

Results Transcriptional profiling of putative stem cells suggested an undifferentiated and slowly cycling phenotype. Genes, encoding transcripts involved in self-renewal of stem cells, negative regulation of proliferation via TGF-b signalling, organogenesis and inhibition of the WNT signalling pathway were overrepresented, whereas genes responsible for cell division and DNA replication and DNA repair were underrepresented. Markers for cervical stem cells were validated at the protein level, permitting localization of stem cells in a scattered pattern within the basal layer of the cervical epithelium. Isolation and characterization of these cells confirmed an undifferentiated, slowly cycling phenotype with high proliferative potential. We successfully optimized a cervical organ culture model developed in our laboratory, now maintaining original organ architecture, tissue heterogeneity and expression of cellular markers for up to 4 weeks. These cervical explants provided the basis for monitoring virus binding and the course of infection within the regenerating epithelium after exposure to HPV pseudoviruses. Long-term infection was detected in only a small number of cells within the basal cell layer. These cells possess characteristics and functional properties of stem cells, thus suggesting that stem cells are the targeted cell type to achieve viral persistence. Conclusion Our results permit the first time phenotypic and functional distinction of viable cervical stem cells, describe their localization within the human cervical epithelium and define their role in HPV-associated carcinogenesis. We describe the development of the first cervical organ culture system maintaining all cell types of squamous epithelium over a period of 4 weeks and permitting monitoring of high risk HPV infection. Data recruited from this model suggest that infection of stem cells within the cervical epithelium is indeed necessary to establish long-term infection. These findings represent an important step forward to thoroughly define the role of stem cells in HPVassociated carcinogenesis, not only within the cervix but also in other HPV-related malignancies, such as anal, vulvar and oropharyngeal cancers. Insights may be gained into the pathogenesis of cancers attributable to other oncogenic viruses, such as hepatocellular cancer and Burkitt lymphoma. Identification and characterization of tumour stem cells driving overall proliferation and malignant potential will be the key to developing effective treatments in the future. This project will continue until fall 2011. A follow-on project to translate results into an in vivo animal model is planned. Dr. Astrid Baege Klinik für Gynäkologie UniversitätsSpital Zürich Frauenklinikstrasse 10 CH-8091 Zürich Phone +41 (0)44 255 11 11 astrid.baege@usz.ch Ballmer Peter E. Influence of a nutritional intervention on clinical course and quality of life in cancer patients (OCS 02000-02-2007) Involuntary loss of body weight is common in patients presenting with malignant tumours. The disease itself and various oncological treatments may further deteriorate the nutritional status. A deficient nutritional status potentially increases the side effects of the therapy and may increase the complication rate and length of hospital stay and decrease the effect of antitumoural therapies. In a pilot-study with undernourished hospitalized patients we showed that intensive nutritional counselling increased energy intake and protein intake as well as quality of life. The present study investigated the impact of nutritional intervention on energy and protein intake and quality of life in malnourished cancer patients in the ambulatory setting. The primary endpoints were improvement of the energy and protein intake and of quality of life. Methods Undernourished outpatients with cancer were randomised in two groups. One group was individually counselled by a professional dietician, and the other group received the usual oncological care without specific nutritional intervention. Study duration was 6 months. Patients in the counselled group were individually counselled and supported during the first 3 months. Study measurements were carried out at baseline and after 6 weeks, 3 and 6 months. Energy and protein intake was assessed at each study visit with dietary records, and quality of life was measured by standardized protocols (EORTC-QLQ-C30 and a visual analogue scale concerning dietary items). Results and Recommendations The study showed that the nutritional intervention significantly increased energy and protein intake. In contrast to our pilot study with hospitalized patients, there was no effect on quality of life. We hypothesize that the nutritional intervention may have been too late to result in a beneficial effect of the increased dietary intake on quality of life in these patients with already advanced cancer disease and deteriorated nutritional status. We therefore suggest that individual nutritional support be initiated at an early stage of the disease to avoid or delay nutritional deterioration; however, this hypothesis needs to be proven in a new clinical trial. Prof. Dr. Peter E. Ballmer Klinik für Innere Medizin Departement Medizin Kantonsspital Winterthur Brauerstrasse 15 CH-8401 Winterthur Phone +41 (0)52 266 23 01 Fax +41 (0)52 266 47 06 peter.ballmer@ksw.ch 125

126 Benhattar Jean Identification of biomarkers for early cancer detection in Barrett s esophagus patients using methylation profiles and the Wnt pathway (OCS 01638-02-2005) Barrett s oesophagus (BE) is a lesion resulting from chronic gastro-oesophageal reflux disease, in which the stratified squamous epithelium of the oesophagus is replaced by metaplastic columnar epithelium that predisposes to the development of oesophageal adenocarcinoma. Barrett s oesophageal adenocarcinoma is characterized by one of the most rapidly increasing incidence rates of any cancer in the Western world. Despite advances in staging and treatment, this malignancy is highly lethal, with a 5-year survival rate of less than 10 %. Early detection represents one of the most promising approaches to reducing the growing cancer number, as already demonstrated in other malignancies such as cervical and breast cancer. Early detection research has recently been revitalized by the advent of novel molecular technologies that can identify cellular changes at the genome level. These molecular technologies offer many new opportunities for developing biomarker-based tests that could be used in addition to or in substitution for some of the existing screening tests. A variety of molecular genetic and epigenetic events appear to coincide in the progression of BE to adenocarcinoma. Our research activities are focused on the detection and the development of epigenetic biomarkers that can predict the likelihood of the neoplastic progression in Barrett s patients. To increase knowledge on methylation changes, a Methylation Ligation-dependent Macroarray (MLM) has been generated. This array-based DNA methylation profiling allows the screening of 45 promoter genes on 20 samples at the same time. This technology can be used: 1) in clinical trials to identify methylation profiles for appropriate drug delivery; 2) to distinguish pathologies with or without potential progressive evolution; 3) for metastases prognosis; and 4) for diagnosis. In oesophageal adenocarcinoma, aberrant methylation of promoter regions occurs with a high frequency not only in advanced cancer but also in BE. Hypermethylation of a subset of tumour suppressor gene promoters strongly predicts progression to high-grade dysplasia or cancer in patients with BE. On the other hand, rare occurrence of tumour suppressor gene hypermethylation is associated with a benign course in BE. Our research also focuses on the aberrant activation of the Wnt signalling pathway, which is a key feature of many cancers. While mutations in APC or b-catenin are exceptional in Barrett s adenocarcinomas, alterations of upstream components, such as overexpression of Wnt2 ligand or downregulation by promoter methylation of several Wnt antagonists, may play dominant roles in the activation of the Wnt pathway. Our data suggest that inhibiting the Wnt pathway could become a new targeted therapy for the treatment of cancers and could therefore be promising for the prevention and cure of oesophageal adenocarcinoma. Furthermore, methylation biomarker-based panel to predict neoplastic progression in BE has potential clinical value in improving both the efficiency of surveillance endoscopy and the early detection of neoplasia. Dr Jean Benhattar Institut universitaire de pathologie de Lausanne (IUP) Centre hospitalier universitaire vaudois (CHUV) Rue du Bugnon 25 CH-1011 Lausanne Phone +41 (0)21 314 71 53 Fax +41 (0)21 314 71 15 jean.benhattar@chuv.ch Bertoni Francesco Evaluation of the tyrosine kinase SYK as a possible therapeutic target in lymphomas (KLS 01835-02-2006) SYK is a non-receptor tyrosine kinase involved in the B-cell receptor (BCR) signalling pathway. When activated, it leads to intracellular calcium mobilization, activation of AKT, mitogen-activated protein kinases (MAPKs) and NFkB. Inhibition of SYK had been proposed as a new promising therapeutic approach for lymphoid neoplasms. In this project we evaluated the efficacy of a series of SYK inhibitors in lymphoma cell lines and primary cells and studied the pattern of SYK expression in mature B-cell lymphomas. Material and methods We exposed cell lines of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and primary cells of a variety of lymphomas to increasing doses of different SYK inhibitors. SYK expression was evaluated on a series of 303 lymphoma biopsies by immunohistochemistry. Results We first evaluated the potentiality of SYK inhibition (Rinaldi et al., Hematological Oncology 2011). Based on our previous data on MCL cell lines (Rinaldi et al., British Journal of Haematology 2006), we first treated six DLBCL cell lines with increasing doses of the SYK inhibitor piceatannol. The cell line that was the most sensitive and that showed a clear dose response had the highest level of SYK, and it presented an extra copy of the locus containing SYK. Three of the 6 DLBCL cell lines and 4 MCL cell lines were then exposed to increasing doses of a potent SYK/ZAP70 inhibitor, NVP, for 72 h. Only the two cell lines expressing high levels of SYK showed an IC50 at a dose suggestive of a SYK-mediated cytotoxic effect. Due to the suggested capacity of the BCR-ABL inhibitor imatinib to bind SYK, MCL and DLBCL cell lines were exposed to the BCR-ABL inhibitors imatinib and nilotinib, which are already in clinical use. No cell line responded to doses of imatinib lower than the concentration clinically achievable and used for chronic myeloid leukemia and other sensitive neoplasms. Still, the two cell lines with

constitutively high SYK levels showed progressive inhibition of cell proliferation, indicating a possible dose-dependent cytotoxic effect. To obtain further data on the relevance of SYK inhibition in lymphoma, we treated 5 lymphoma primary cells derived from DLBCL and 3 from leukemic MALT lymphomas with increasing doses of NVP and piceatannol and with nilotinib at the clinically reachable dose. The data obtained on lymphoma primary cells confirmed the cytotoxic activity of tyrosine kinase inhibitors in lymphoma primary cells, but the heterogeneous pattern of response suggested that the effect could be due to inhibition of molecules other than SYK and contributing to the constitutive BCR signaling. Regarding protein expression in clinical specimens, four patterns of SYK localization were shown to have a peculiar distribution among different types of lymphoma and lymphoid tissues analyzed (Ponzoni et al., Leukemia Research 2011). SYK was statistically significantly more frequently detected mainly or exclusively in the cytoplasm in DLBCLs, splenic marginal zone lymphomas and reactive spleens. The kinase was statistically significantly found mainly or exclusively in the nucleus in MCL. Conclusions Our functional characterization of SYK in lymphoma cell lines and lymphoma primary cells support the design of prospective trials testing different molecules targeting SYK. Our extensive immunohistochemical characterization pointed towards divergent SYK localization in different lymphoma subtypes, suggesting different functions in the different subtypes. Dr. Francesco Bertoni Laboratorio di oncologia sperimentale Istituto oncologico della Svizzera italiana (IOSI) Via Vincenzo Vela 6 CH-6500 Bellinzona Phone +41 (0)91 8200 367 Fax +41 91 8200 397 frbertoni@mac.com

128 Bertoni Francesco Genome-wide DNA profiling as outcome predictor in diffuse large B-cell lymphoma (OCS-1939-8-2006) Diffuse large B-cell lymphoma (DLBCL) represents the most common non-hodgkin s lymphoma in Western countries, and it is a very heterogeneous group of disorders. With current therapies, at least 40 % of the patients are not cured. The aims of the study were to identify genomic lesions predicting response to the current standard therapy, R-CHOP, to characterize DLBCL subgroups and to identify new DLBCL genes. Material and methods The study was performed on 166 DLBCL clinical samples, thanks to an international network of collaborating investigators. Genomic profiles were obtained using the Affymetrix Human Mapping 250k Arrays, and gene expression profiling was done using Affymetrix U133 plus 2.0. Results Genomic losses affecting the short arm of chromosome 8 appeared associated with a poor outcome in patients with DLBCL treated with R-CHOP (Scandurra, Mian, et al., British Journal of Haematology 2010). The role of del(8p) is under evaluation by fluorescence in situ hybridization (FISH) analysis in a large series of patients treated with R- CHOP. By comparing the genomic profiles of DLBCL in immunocompetent individuals versus genomic profiles of HIV-related DLBCL (HIV-DLBCL) and post-transplant DLBCL (PT-DLBCL), we identified a series of previously unknown features of immunodeficiency-related DLBCL (Rinaldi et al., British Journal of Haematology 2010; Capello et al., British Journal of Haematology 2010). We then looked at cases of DLBCL with concordant or discordant bone marrow involvement, an important prognostic factor for DLBCL patients (Chigrinova et al, Hematological Oncology 2010). The main finding was that cases with gains at chromosome 7/7q, a common DLBCL lesion, never had bone marrow involvement. We therefore studied DLBCL cases with these lesions by combining genomic profiling, gene expression profiling and mirna profiling (Chigrinova et al., British Journal of Haematology 2011). Gains affecting chromosome 7, mostly of the whole chromosome, do not directly alter gene expression, but they appear to deregulate a series of mirna mapped on chromosome 7. Finally, to identify new genes involved in the pathogenesis of DLBCL, by combining our array CGH with a mutational screening of NFkB genes performed by Laura Pasqualucci s group in New York, the tumour suppressor gene TNFAIP3/A20 was identified as frequently inactivated in non-germinal centre DLBCL (Compagno et al., Nature 2009). Conclusions We identified lesions predicting the outcome in patients treated with the current standard therapy, and once this is validated in an external series, it might help to provide a patient-tailored therapeutic plan. Also, we characterized different DLBCL subgroups and genomic lesions. Additional work is still ongoing on both the characterization of new DLBCL genes and DLBCL subgroups and the identification of outcome/response predictors. Dr. Francesco Bertoni Laboratorio di oncologia sperimentale Istituto oncologico della Svizzera italiana (IOSI) Via Vincenzo Vela 6 CH-6500 Bellinzona Phone +41 (0)91 820 03 67 Fax +41 (0)91 820 03 97 frbertoni@mac.com Bertoni Francesco Extranodal, nodal and splenic marginal zone B-cell lymphomas: How much are they related to each other? (OCS 02034-02-2007) Marginal zone B-cell lymphomas (MZL) have been divided into 3 distinct subtypes (extranodal MZL of MALT type, nodal MZL, splenic MZL), but the relationship between the subtypes has remained unclear. We performed a comprehensive analysis of genomic DNA copy number changes in a very large series of MZL cases with the main aims of addressing this issue of the subtypes and of identifying new genes involved in MZL pathogenesis. Material and methods The study was performed on 218 MZL clinical samples (25 nodal, 57 MALT, 134 splenic and two not better specified MZL) thanks to an international network of collaborating investigators. Genomic profiles were obtained using Affymetrix Human Mapping 250k Arrays for all cases; gene expression profiling was available for a subset of the samples. Results Regarding the differences among the subtypes (Rinaldi et al., Blood 2011), MALT lymphoma presented gains at 3p, 6p, 18p and del(6q23) significantly more frequently, whereas splenic MZL had del(7q31) and del(8p). Nodal MZL did not show statistically significant differences when compared with MALT lymphoma but lacked the splenic MZL-related 7q losses. Gains of 3q and 18q were common to all three subtypes. Del(8p) was often present together with del(17p). Whereas del(17p) did not determine a worse outcome and del(8p) was only of borderline significance, the presence of both deletions had a highly significant negative impact on the outcome of splenic MZL.

Regarding new genes, in collaboration with Riccardo Dalla Favera s group in New York we identified the tumour suppressor gene TNFAIP3/A20, an inhibitor of the NFkB pathway, as being frequently deleted and mutated, especially in MALT lymphomas (Novak et al., Blood 2009). We also studied the relationship between immunogenetics and genomic lesions in splenic MZL (Rinaldi et al., British Journal of Haematology 2010). Splenic MZL express mutated (M-) or unmutated (U-) immunoglobulin heavy chain (IGHV) genes. We combined SNP arrays and IGHV sequencing in 83 cases. Clinical features and outcome were similar between U- and M-IGHV cases. Recurrent lesions frequency was higher in U-IGHV cases, including poor prognosticators. Frequencies differed among cases bearing individual VH genes or lambda light chains. We also studied the role of antigen stimulation in splenic MZL (Zibellini et al., Haematologica 2010). The occurrence of stereotyped B-cell receptors was investigated in 133 SMZL (26 HCV + ) and compared with 4,414 HCDR3 sequences from public databases. Sixteen SMZL (12 %) showed stereotyped BCR; 8 % of SMZL sequences retrieved from public databases also belonged to stereotyped HCDR3 subsets. Three categories of subsets were identified: 1) SMZL-specific subsets ; 2) Non-Hodgkin s lymphoma-like subsets ; and 3) CLL-like subsets. Immunoglobulin 3D modelling of 3 subsets revealed similarities in antigen binding regions not limited to HCDR3. Conclusions We identified the different patterns of genomic aberrations in MZLs, thus aiding differential diagnosis. We identified a lesion predicting a poor outcome in splenic MZLs, which could be useful to better manage patients. Also, we identified a new gene strengthening the NFkB pathway as an important therapeutic target for these patients. Splenic MZLs present distinctive features in terms of immunogenetics. Additional studies are ongoing, and data will be reported in the future. Dr. Francesco Bertoni Laboratorio di oncologia sperimentale Istituto oncologico della Svizzera italiana (IOSI) Via Vincenzo Vela 6 CH-6500 Bellinzona Phone +41 (0)91 820 03 67 Fax +41 (0)91 820 03 97 frbertoni@mac.com Bohlius Julia Individual patient data meta-analysis on the effects of erythropoiesis-stimulating agents in cancer patients (OCS 02146-10-2007) Patients with cancer have an increased risk for anaemia, which may negatively impact their quality of life (QoL). Erythropoiesis-stimulating agents (ESAs) reduce anaemia in cancer patients and may improve QoL, but there are concerns that ESAs might increase mortality. Study aim We collected patient data from randomised controlled trials to evaluate the effect of ESA on mortality and survival in patients with cancer and to identify subgroups of patients that may benefit from ESAs. Methods We identified randomised controlled trials comparing epoetin alfa, epoetin beta or darbepoetin alfa plus red blood cell transfusions versus transfusion alone, for prophylaxis or therapy of anaemia in patients with cancer receiving chemotherapy, radiotherapy or no anticancer therapy. Study investigators from eligible trials were invited to collaborate and submit raw data of their studies. Main analyses were defined in a peer-reviewed protocol and a statistical analysis plan. A steering committee consisting of clinicians and methodologists reviewed results and agreed on their interpretation. The raw patient-level data were meta-analyzed by independent statisticians at two academic departments, using fixed-effects and random-effects meta-analysis. Primary endpoints were onstudy mortality, defined as duration of ESA study plus 1 month follow-up, and overall survival, defined as the longest follow-up available. Analyses were conducted separately for all patients with cancer regardless of anticancer therapy and for patients receiving chemotherapy. Tests for interactions were used to identify differences in effects of ESAs on mortality and survival for pre-specified subgroups. Findings A total of 13,933 patients with cancer from 53 trials were analyzed: 10,411 patients were scheduled to receive chemotherapy, 799 radiotherapy, and 737 radiotherapy combined with chemotherapy. 1,690 patients received no anticancer treatment during the ESA study, and 266 received other treatment modalities. 1,530 patients died on study and 4,993 overall. Including all patients with cancer regardless of anticancer therapy, ESAs increased on-study mortality (hazard ratio [HR] 1.17; 95 % confidence interval [CI] 1.06 1.30) and worsened overall survival (HR 1.06; 95 % CI 1.00 1.12), with little heterogeneity between trials (I 2 0 %, p=0.87 and I 2 7.1 %, p=0.33, respectively). Restricting the analysis to patients receiving chemotherapy, the HR for on-study mortality was 1.10 (95 % CI 0.98 1.24) and 1.04 (95 % CI 0.97 1.11) for overall survival. There was little evidence of a difference between trials of patients receiving different cancer treatments (p for interaction=0.42). 129

130 Interpretation ESA treatment in patients with cancer increased on-study mortality and worsened overall survival. For patients undergoing chemotherapy, the increase was less pronounced, but an adverse effect could not be excluded. Dr. Julia Bohlius Forschungsgruppe Krebs Institut für Sozial- und Präventivmedizin (ISPM) Universität Bern Finkenhubelweg 11 CH-3012 Bern Phone +41 (0)31 631 35 10 jbohlius@ispm.unibe.ch Carbone Giuseppina Functional and clinical implications of deregulated expression of ETS transcription factors in prostate cancer (OCS 01913-08-2006) Cancer of the prostate is a leading cause of cancer death in Western countries. There is great need to understand the factors governing disease progression and identify new therapeutic strategies. Transcription factors of the ETS family have emerged as important elements in the pathogenesis of prostate cancer. About half of prostate cancers harbour chromosomal translocations involving ETS genes. ETS factors act as nodal points of various signalling pathways controlling cell proliferation, differentiation and survival. In many tissues, ETS factors constitute a complex network of transcriptional regulators with biological responses depending on the balance between factors exhibiting similar or opposite functions. Our hypothesis is that an endogenous network of ETS factors controls to a significant extent the differentiation status of prostate epithelial cells. An altered balance between these ETS factors, which may result from environmental, genetic or epigenetic events, could promote cell transformation and drive tumour progression. Objectives The overall goal of this project was to understand the functional and clinical implication of ETS transcription factors in prostate cancer initiation and progression. Methods To reach our goals we applied an integrative approach that combines translational and bioinformatic studies in prostate cancer tumours with experiments in vitro in transgenic cell lines and in vivo in mouse models. We performed gain-of-function and loss-of-function studies using transgenic cell lines. Cell phenotypes were evaluated with a variety of cellular assays that measure growth, cell cycle, apoptosis, cell migration, invasion and stem cell-like properties. Biochemical assays such as chromatin immunoprecipitation were used to evaluate direct promoter occupancy by ETS factors and histone modifications in cells and also in prostate cancer specimens. To define the ETS transcriptional network, we applied genomic tools such as microarray data from prostate cancer patients to perform differential gene expression and correlation analysis. Results The results of our studies substantially advanced our understanding of the functional and clinical role of ETS factors in prostate cancer. We showed that additional ETS factors, besides the known translocated ETS genes, are frequently deregulated in prostate tumours and may contribute significantly to prostate tumourigenesis. We showed for the first time that the epithelial-specific ETS factor ESE3 is frequently underexpressed in prostate tumours and, in experimental models, acts as tumour suppressor gene. Further, our studies demonstrated for the first time the activation of ESE1 in prostate tumours. Based on the ETS alterations identified by array and qrt- PCR data, we divided tumours in subgroups with predominant deregulation of either ERG, ESE1 or ESE3. A fourth group included tumours that had normal-like levels of ETS genes (NoETS). Additional bioinformatic analyses were done to determine whether distinct transcriptional profiles were associated with the prostate cancer subgroups identified on the basis of ETS expression patterns using differential gene expression analysis. ERG and ESE3 tumours had robust signatures with the largest number of differentially expressed genes. This analysis allowed us to uncover the transcriptional network of selected ETS factors in prostate tumours. Further, by integrating genomic data and functional assays in cells, we established a direct link between aberrantly expressed ETS factors and epigenetic reprogramming of the prostate cancer transcriptome. An important finding of our study was the demonstration that the Polycomb group protein EZH2 is a direct target of oncogenic and tumour suppressor ETS factors, like ERG and ESE3. Further, we showed that EZH2 is a key player in transcriptional silencing of the Nkx3.1 tumour suppressor gene. This may represent a general mechanism linking aberrantly expressed ETS with deregulation of epigenetic pathways and reprogramming of prostate epithelial cell transcriptome during tumourigenesis. Clinical relevance for patients The presence of prostate cancer subgroups with distinct ETS expression patterns and biological features may have important implications and suggests that assessment of ETS expression levels might be useful to distinguish tumours with different clinical outcome. Further, the link between altered ETS factors activity and EZH2 mediated epigenetic gene silencing may suggest selective therapeutic strategies for prostate cancer. Project Coordinator Dr. Giuseppina Carbone Laboratorio di oncologia sperimentale Istituto oncologico della Svizzera italiana (IOSI) Via Vincenzo Vela 6 CH-6500 Bellinzona Phone +41 (0)91 820 03 66 Fax +41 (0)91 820 03 97 pina.carbone@irb.unisi.ch

De Libero Gennaro Lipid-specific T cells against leukaemic blasts (KLS 02211-02-2008) We identified highly polar lipid fractions derived from THP1 AML and C1R LCL cell lines able to stimulate two different CD1c-restricted T cell clones. These fractions were obtained using two different procedures from total cellular lipids, extracted according to the Folch method. LC-MS-MS analysis of the fractions confirmed the presence of several ion masses in the biologically active ones, and some of these masses were shared between the stimulatory fractions, independently of the procedure used. However, the low yield and purity of active lipids achieved using both methods did not allow us to identify the structures of these molecules. Therefore, we developed a new extraction procedure and established a new HPLC purification strategy. Using this novel method, we divided total lipids into 10 different fractions according to their polarity and charges. Only one fraction strongly stimulated the selected T cell clones with high efficacy and potency. The antigenic capacity of this fraction was further confirmed by CD1c plate-bound assays, in which soluble recombinant CD1c molecules were attached to plastic wells, loaded with the fraction and then used to stimulate T cell clones. The high and specific T cell clone activation induced by fraction-loaded CD1c complexes clearly suggested that contained lipids behave as minimal antigens and do not require processing by APC to become immunogenic. The LC-MS-MS profile of the stimulatory fraction revealed the presence of few molecular species. In order to separate these molecules and to isolate the active ones, we further sub-fractionated the T cell activating fraction by HPLC and LC-MS-MS. Three out of 60 sub-fractions showed potent stimulatory activity, and in each of them only one predominant molecular species was present, as indicated by the MS-MS analysis performed in real time during the collection. A further LC-MS-MS analysis, performed with two different mass spectrometers (ESI ion trap and triple quadrupole) in both positive and negative ionisation modes, indicated that two of these molecules are characterized by a fragmentation pattern in part similar to that of lysophosphatidic acid. To confirm this finding and to assign exact molecular mass to these compounds, we analyzed the active sub-fractions with an Orbitrap mass spectrometer equipped with a nanospray system. This allowed us to confirm the structure of the previously identified molecules and to determine length and features of the single acyl chain present in the two active molecules. In a new series of studies we performed nuclear magnetic resonance (NMR) analysis of the antigenic lipid compounds after extensive purification. NMR confirmed the proposed structure and provided complementary information on the nature of lipids. All together, these findings show that a unique lipid with a structure never described before accumulates in leukaemic cells. This novel lipid family seems to be very abundant in rapidly proliferating cells. It will be important to investigate the metabolic pathways responsible for the synthesis of these lipids and how they are regulated in leukaemic cells. Prof. Dr. Gennaro De Libero Experimentelle Immunologie Departement Biomedizin Universität Basel Hebelstrasse 20 CH-4031 Basel Phone +41 (0)61 265 23 65 gennaro.delibero@unibas.ch Dirnhofer Stephan Inducing cell death in apoptosisresistant hematological tumors: Impact on diagnosis and therapeutic intervention (OCS 01792-10-2005) Study outline Patients with DLBCL (diffuse large cell B cell lymphoma) and AML (acute myeloid leukaemia) have been evaluated for potential therapeutic markers regarding CD44 and its interaction partners. DLBCL and AML belong to the most abundant lymphomas and leukaemias with a wide-ranging prognosis. A long-term goal is to develop tailor-made therapies for defined groups of patients to allow for more potent and specific treatment. Study design Our main objective was to find out how the resistance against apoptosis of malignant hemopoietic cells (from DLBCL and AML patients) can be favourably affected, i.e. abolished. Study results We showed that co-expression of CD44 variant isoforms (all isoforms analyzed) and CD168 (RHAMM, receptor for hyaluronan mediated motility) identifies a subgroup of patients with DLBCL who have a very adverse prognosis. This prognosis was independent of the international prognostic index (IPI). Expression of CD168 RHAMM in AML patients turned out to be a central prognostic indicator. When CD168 is expressed in association with CD44, active caspase-3 (as indicator for spontaneous apoptosis) and the oncogenic transcriptions factors STAT-3 and -5 a very adverse prognosis is implied for these patients. Benefit for the patient A therapeutic application of antibodies against surface molecules such as CD44 and CD168 could exert a blocking effect on the resistance against apoptosis. The group of patients in which CD44 and CD168 are co-expressed could have better survival odds with accordingly adjusted therapies. When patients with AML receive stem cell therapies the beneficial graft vs. leukaemia (GvL) reaction indicates the importance of leukaemia associated antigens (LAA). In search for potent LAA in patients with AML, CD168 is an auspicious candidate for specific vaccination. 131

132 Our results could pave the way for further prospective analyses in larger cohorts of patients and allow for the development of innovative and target-oriented therapies. Prof. Dr. Stephan Dirnhofer Institut für Pathologie Universität Basel Schönbeinstrasse 40 CH-4003 Basel Phone +41 (061 265 27 89 Fax +41 (0)61 265 31 94 sdirnhofer@uhbs.ch Doucey Marie-Agnès Functional and biochemical characterization of human monocyte-like circulating cells in breast cancer patients: Relevance to tumor growth and angiogenesis (OCS 02069-04-2007) Tumour angiogenesis is a prominent mechanism driving tumour development and progression, and drugs targeting VEGF (vascular endothelial growth factor) and its receptors have been approved for the treatment of human cancer. However, primary and acquired resistance to VEGF pathway blockade represents a critical obstacle to further improvement of anti-angiogenic therapy and calls for additional therapeutic targets. Myeloid cells are such candidates. Indeed, tumour-mediated recruitment of myeloid cells with angiogenesis and tumour-promoting activity is one of the most remarkable observations made in experimental oncology in recent years. The presence of tumour-associated macrophages was shown to be associated with unfavourable prognosis in cancer patients and correlated with increased microvessel density in a variety of human solid tumours. More recently, Tie-2-expressing monocytes (TEM) were identified in humans and mice as a functionally distinct myeloid-derived cell population with potent proangiogenic activity. In experimental mouse models, TEM ablation fully suppressed angiogenesis, thus making them attractive targets for anti-angiogenic therapies. However, to date, the molecular basis of TEM proangiogenic and protumoural activities is largely unknown. Thus, the goal of this study was to unravel tumour specific signals and associated TEM pathways supporting TEM functions in early breast cancer. This approach represents the first step to TEM targeting in anti-cancer therapies. Methods and findings We examined TEM in peripheral blood and tumours of patients with early breast cancer. We reported that tumour TEM specifically triggered the initial phase of breast tumour vascularization, whereas other myeloid cell populations are associated with sustained breast tumour angiogenesis. Using mouse corneal vascularization assay, we reported that tumour TEM consistently displayed a higher proangiogenic activity relative to their blood counterparts, suggesting that the tumour microenvironment shapes TEM phenotype and functions. Indeed, we showed that the expression levels of Tie-2, VEGFR1 and TGFR1 at the surface of patient TEM represent a proangiogenic phenotypical signature specifically induced by the tumour microenvironment. We used TEM differentiated in vitro from CD34 + haematopoietic precursors to identify the tumour signals controlling TEM phenotypical signature and proangiogenic activity. Examination of 12 combinations of angiogenic and inflammatory ligands revealed that TNF-a, PlGF and Ang-2 synergistically promote TEM proangiogenic function. The synergistic effect of these signals relies on cross-talks between TNFR1, VEGFR1 and Tie-2 pathways. Tie-2 and VEGFR1 pathways cooperate and compensate each other to control TEM proangiogenic function, whereas TGFb impaired it. Further, we validated these effects in patient TEM and reported that bloodcirculating patient TEM treated with synergistic ligands increased their proangiogenic activity and shifted their paracrine profile toward angiogenesis. Importantly, guided by the understanding of this pathway interplay, we demonstrated that the combination of TGFb with a Tie-2 inhibitor abrogates the proangiogenic activity of TEMderived from patient tumours. Conclusions and patient benefit This study highlighted the contribution of TNF-a, PlGF and Ang-2 as specific tumour microenvironmental signals in TEM proangiogenic and protumoural functions and identified TGFb/Tie-2 axis as a potential therapeutic target to abrogate the proangiogenic function of TEM at breast tumour sites. These results open up new opportunities for anti-angiogenic cancer therapies by targeting TEM and suggest that these cells may contribute to resistance to VEGF pathway blockade. Dr Marie-Agnès Doucey Centre pluridisciplinaire d oncologie (CePO) Université de Lausanne Le Génopode CH-1015 Lausanne 15 Phone +41 (0)21 692 39 47 marie-agnes.doucey@unil.ch Dubey Raghvendra K. Pathophysiological role of estrogen metabolism in breast cancer (OCS 01551-08-2004) Breast cancer is one of the leading causes of premature death in women worldwide. Although exposure to increased oestrogen is an established risk factor in both young women and postmenopausal taking hormone therapy (HT), the mechanisms involved (cancer progression / metastasis) are unclear. Oestrogens not only have a physiological and biological role but also are implicated in the development of breast cancer by simultaneously stimulating abnormal cell proliferation and gene expression potentially via the oestrogen receptor (ER). The fact that ERs are expressed in breasts of most women but not all of them get oestrogen-induced cancer suggests that an alternative pathway that counteracts the carcinogenic effects of oestrogens may be active, and lack of this pathway may make women more susceptible to oestrogen induced breast cancer. In this context, endogenous estradiol is metabolized to methoxyestradiol (2-ME), a potent anticarcinogenic and antimitogenic agent. Since breast cells express enzymes that convert estradiol to 2-ME, this may serve as a pathway to counteract ER-mediated proliferative actions of estradiol. Hence, using molecular and pharmacological approaches, the objective of this project

was to explore whether sequential conversion of 17bestradiol to 2-ME is an intrinsic growth inhibitory pathway that counteracts/suppresses the ER-dependent proliferative actions of 17b-estradiol. Results Growth studies using ER-positive breast cancer cells revealed that estradiol has a biphasic effect on their growth, with proliferative and inhibitory effects at low (physiologic) and high concentrations respectively. Importantly, studies with ER-negative cells and ER antagonists show that the proliferative phase is ER-dependent, whereas the inhibitory effects of estradiol are mediated via conversion of estradiol to 2ME. Molecular and gene-silencing studies provide evidence that the inhibitory effects of estradiol are mediated by 2-ME via upregulation of p21, a negative regulator of cell cycle. Potential Implications Because 2-ME, an endogenous non-estrogenic oestrogen metabolite, counteracts/suppresses the proliferative/carcinogenic actions of estradiol, this non-estrogenic and non-carcinogenic oestrogen metabolite could be employed for the prevention of breast cancer. Metabolic disorders and inter-individual differences in estradiol metabolism might affect the balance between the proliferative and anti-proliferative pathways and define the potential risk for an individual to develop breast cancer. Moreover, assay of 2-methoxyestradiol or the key enzymes responsible for 2-ME formation, i. e. catechol-o-methyltransferase, in biopsy tissues may serve as a diagnostic marker in women with potential risk of oestrogen associated breast cancer. Finally, in postmenopausal women using hormone replacement therapy, 2-ME could be employed for prevention of cardiovascular disease without increasing the risk of cancer. Finally, the presence of the negative regulatory metabolic pathway may also help explain the protective effects of oestrogens and the deleterious effects of oestrogens plus medroxyprogesterone on breast cancer in the recently concluded Women s Health Initiative (WHI) study, as medroxyprogesterone inhibits the formation of 2-hydroxyestradiol, the precursor of 2-methoxyestradiol. Prof. Dr. Raghvendra K. Dubey Klinik für Reproduktions-Endokrinologie UniversitätsSpital Zürich Frauenklinikstrasse 10 CH-8091 Zürich Phone +41 (0)44 255 86 08 raghvendra.dubey@usz.ch Frattini Milo Characterization of EGFR deregulation and EGFR downstream cascade in colorectal cancer patients, and relationship to new targeted therapies (OCS 01921-08-2006) Colorectal cancer (CRC) is the second leading cause of cancer-related death in Western countries. Newer therapeutic options for treating metastatic CRC (mcrc) include targeted biological therapies, with those against epidermal growth factor receptor (EGFR) showing promising data. Cetuximab and panitumumab are two monoclonal antibodies that block EGFR and, therefore, block its activation and the transduction cascade of mitogen signals. EGFR-targeted therapies have significantly increased the follow-up of affected patients but are effective only in 10-20 % of cases. In addition, they are quite toxic and expensive. Objective As no molecular markers able to predict the efficacy of EGFR-targeted therapies were available at the time, the overall goal of this research project was to better understand the significance of deregulation of EGFR (the target) and/or proteins of its downstream signalling cascade (PTEN, KRAS, BRAF, PIK3CA), on EGFR-targeted therapies response in CRC patients. Methods and procedure A series of patients with mcrc were identified in Ticino and then treated with cetuximab or panitumumab. Patients tissue specimens were evaluated for EGFR gene status by fluorescence in situ hybridization, for PTEN protein expression by immunohistochemistry and for KRAS, BRAF and PIK3CA mutational status by direct sequencing. A series of 44 patients with primary CRC and paired distant metastatic lesion were investigated with the same markers. Results In our cohort, we found that a normal gene status of EGFR, the presence of KRAS mutations, BRAF mutations, PIK3CA mutations and the PTEN loss of expression all represent independent predictive markers of resistance to EGFR-targeted therapies, because they occurred only in patients who experienced no response to these drugs. By comparing the molecular profile of primary tumour with that of the metastatic lesion, we observed some differences, especially at EGFR gene status level, thus indicating that it should be better to perform analyses of metastatic specimens than analyses of primary tumours. Recommendations and patient benefit Our results were subsequently confirmed by other studies and therefore concurred with the definition of KRAS as a molecular marker that has to be tested before considering the use of cetuximab or panitumumab as a treatment. The international agencies FDA and EMA approved KRAS testing as a prerequisite before drug administration. The other markers, due to either low frequency of alteration or to lack of standardized methodologies, are currently on stand-by. Therefore, at least 30 % of patients (characterized by KRAS mutation) are not treated with drugs and can be addressed with new combinatorial treatments or 133

134 new drugs that specifically target KRAS and that are now entering clinical trials. As a corollary, KRAS testing decreases the cost of the management of these patients. Dr. Milo Frattini Laboratorio di diagnostica molecolare Istituto cantonale di patologia (ICP) Via in selva 24 CH-6600 Locarno Phone +41 (0)91 816 08 05 Fax +41 (0)91 816 07 19 milo.frattini@ti.ch Gautschi Oliver Regulation of ld1 expression by Src in cancer: Clinical implications (KLS 02164-02-2008) Invasion and metastasis are important hallmarks of cancer, but only few drugs are currently available that target these mechanisms in patients. Most anticancer drugs target cell proliferation and survival. Members of the Src family of non-receptor tyrosine kinases are part of the focal adhesion complex, which mediates migration and invasion in normal and cancer cells. Src is frequently activated in human cancer by growth factor and cytokine receptors. Therefore, Src is a promising cancer drug target, and several Src kinase inhibitors are currently in clinical trials. Although preliminary results indicate that these agents have clinical activity against solid tumours including lung cancer, the activity appears to be limited to a group of patients. As for many other molecular targeted agents, predictive factors for Src inhibitors remain to be identified. The aim of our project is to better understand the Src signalling pathway in human lung cancer, which may lead to a rational development of Src inhibitors in oncology. Using pharmacological small-molecule Src kinase inhibitors, viral vectors carrying Src mutant constructs and gene expression microarrays, we previously identified inhibitor of differentiation 1 (ID1) as a new and functionally relevant target gene of Src kinase in human lung cancer cells. The ID1 gene mediates stem cell function and is a potent regulator of cancer cell invasion. More recently, using an established lung cancer biobank, we demonstrated that Src and ID1 are frequently and strongly co-expressed in primary human lung cancer, compared with matched lung tissue. ID1 expression correlated with poor tumour differentiation and with expression of matrix metalloproteinase 9 (MMP9). Interestingly, ID1 was also overexpressed in pre-invasive lung lesions. In lung cancer cell lines, forced expression of ID1 enhanced Matrigel invasion and caused resistance to Src kinase inhibitors, which was supported by preliminary animal experiments. Using Src inhibitors and microarrays, we identified two micrornas that target ID1 expression. Manipulation of these micrornas in lung cancer cell lines again changed the effect of Src kinase inhibitors on migration and invasion. Tumour microrna expression in patient samples inversely correlated with ID1 expression and with patient survival. These results suggest that ID1 and micrornas are dysregulated in lung cancer and can modulate and predict the activity of Src kinase inhibitors. As a consequence, ongoing work includes further experiments to confirm the predictive value of ID1 and micror- NAs for Src inhibitors in preclinical models of metastatic lung cancer. Further efforts are focused on the pharmacological targeting of micrornas to develop rational drug combinations with Src inhibitors and other targeted agents. Dr. Oliver Gautschi Departement für klinische Forschung Universität Bern Inselspital Murtenstrasse 35 CH-3010 Bern Phone +41 (0)31 632 25 18 Fax +41 (0)31 632 09 46 oliver.gautschi@onkologie.ch Heim Markus Hermann Hepatocarcinogenesis in chronic hepatitis C (OCS 02192-02-2008) Background Chronic hepatitis C (CHC) is a major cause of liver disease worldwide and a risk factor for cirrhosis and hepatocellular carcinoma (HCC). Regardless of its aetiology, cirrhosis is a major clinical risk factor for HCC, and indeed, hepatitis C virus (HCV) associated HCC generally develops in patients with cirrhosis. There is also evidence for HCV specific tumourigenic pathways, mainly involving HCV core and NS5A proteins. However, the molecular pathways responsible for HCV induced hepatocarcinogenesis have not yet been characterized. A potential tumourigenic pathway could involve protein phosphatase 2A (PP2A) and protein arginine methyltransferase 1 (PRMT1), since both enzymes are dysregulated in chronic hepatitis C and both enzymes have been involved in chromatin remodelling and DNA damage repair. Aim The aim of the studies was to elucidate the role of PP2A overexpression and of PRMT1 inhibition for carcinogenesis. Methods We used cell lines that allow the inducible expression of hepatitis C virus proteins (UHCV57.3) and of the catalytic subunit of PP2A (UPP2A-C8) as well as Huh7.5 cells infected with recombinant cell culture-derived HCV (HCVcc) to study epigenetic histone modifications and DNA damage repair. We also investigated if the methyl group donor S-adenosyl-L-methionine (SAMe) could reverse the HCV induced changes. Results The induction of viral proteins, the overexpression of PP2Ac or the infection of Huh7.5 cells with HCVcc resulted in an inhibition of histone H4 methylation/acetylation and histone H2AX phosphorylation in a significantly changed expression of genes important for hepatocarcinogenesis and inhibited DNA damage repair. These changes were partially reversed by the treatment of cells with the methyl-group donor S-adenosyl-L-methionine (SAMe).

Conclusion The correction of defective histone modifications by S- adenosyl-l-methionine makes this drug a candidate for chemo-preventive therapies in patients with chronic hepatitis C who are at risk for developing hepatocellular carcinoma. Prof. Dr. Markus Hermann Heim Klinik für Gastroenterologie und Hepatologie Universitätsspital Basel Petersgraben 4 CH-4031 Basel Phone +41 (0)61 265 51 74 markus.heim@unibas.ch Heinzelmann-Schwarz Viola Detection of anti-glycan autoantibodies as biomarkers of high stage serous ovarian cancer; acronym: GOS-study (OCS 02115-08-2007) Serous ovarian cancer (SOC) is the most common subtype of ovarian cancers in the Western world, contributing to its high overall mortality rate. It is known that altered glycosylation of cell-surface proteins and lipids as well as extracellular proteins are associated with transformation into a cancer, producing specific tumour-associated antigens. Utilizing a printed glycan array (PGA), we aimed to identify abnormal patterns in serum samples of healthy controls and patients with SOC in order to develop a new generation of tumour markers for the early detection of ovarian cancer. Serum samples were collected from healthy control patients with known negative intra-operative findings (n=26) and patients with advanced SOC (n=16) at University Hospital Zurich and Limmattal Hospital following ethical approval. The printed glycan array incorporates 211 carbohydrate structures, which are printed on glass

136 slides in two different concentrations. After incubation of samples, bound antibodies were detected via a fluorescence signal. Data were preprocessed and statistically analyzed. Using this array technology, we were able to identify a panel of blood antibodies with different levels in healthy controls compared to SOC. Two antibodies had an identical core structure, which had significantly lower antibody levels in patients with SOC. The combination of five antibodies reached significance for the detection of SOC with an excellent discrimination capability. Our data indicate that using printed glycan array technology we are able to recognize the transformation of a cancer via its abnormal carbohydrate binding, hereby measuring an individual person s immune response. With this technology we are able to define an individual profile for patients with SOC. Further experiments are ongoing to validate these results in a double-blind manner for a bigger independent patient cohort. Dr. Viola Heinzelmann-Schwarz Translational Research Group Klinik für Gynäkologie Medizinbereich Frau-Kind UniversitätsSpital Zürich Frauenklinikstrasse 10 CH-8091 Zürich Phone +41 (0)44 255 5374 Fax +41 (0)44 255 4553 viola.heinzelmann@usz.ch Herrmann Richard The SAKK Initiative for regional hospitals (KLS 02067-04-2007) The SAKK initiative for regional hospitals aimed to provide strategic, operational and financial support to middlesized regional hospitals to give patients with cancer living in peripheral areas the opportunity to be treated within a clinical trial. The Swiss Group for Clinical Cancer Research (SAKK) has conducted clinical trials in oncology since 1965. Today, thanks to medical progress in general and clinical research in particular, many cancer types are detected at early stages and will be successfully cured. Hence, the number of patients with cancer requiring therapeutic intervention has increased rapidly. As a consequence, most hospitals have expanded their infrastructure and personnel qualifications to ensure adequate treatment of patients with cancer. But not all hospitals offer clinical trials, since clinical research is very expensive and increasing administrative and regulatory requirements impede the conduct of clinical trials. In Switzerland research-related structures in the clinical setting exist mainly at the university hospitals and the larger cantonal hospitals, whereas regional hospitals are mostly oriented towards service provision and not research. In general, patients with early stage cancer are treated at regional hospitals, whereas patients with an advanced stage or rare disease that requires intensive treatment are commonly treated at a university hospital or large cantonal hospital, where the patients also have access to clinical trials. The risk of this practice is that clinical trial results may not present a real-world view of how these treatments and drugs actually work in patients populations. Regional hospitals can offer a much more realistic picture of the efficacy and safety of a treatment or drug. This potential bias might be reduced by offering patients the possibility to access clinical trials at their regional hospitals. To enforce clinical cancer research at regional hospitals, SAKK initiated the middle-sized hospitals project. Eight hospitals met the requirements of the initiative (Spitalzentrum Biel, Hôpital fribourgeois, Kantonsspital Graubünden, Klinik Hirslanden Zürich, Kantonsspital Luzern, Stadtspital Triemli, Centre hospitalier du centre du Valais, Kantonsspital Winterthur) and received strategic, operational and financial support to set-up the required structures to perform clinical cancer research. The hospitals invested grant money to hire a data manager who supports the medical staff in all administrative and coordinative aspects of a clinical trial. The funded hospitals all started to participate in SAKK trials shortly after project start, and their activities have increased markedly over the last three years. In 2010 the eight hospitals recruited 242 patients into clinical trials coordinated by SAKK out of a total of 787 patients. Clinical cancer research performed by SAKK cares about the interest of the patients and addresses research questions related to practical work. In addition, cancer treatment within a clinical trial complies with medical treatment guidelines and is a quality measurement. As a direct result of the SAKK initiative, more cancer patients have access to clinical trials and thereby to treatment of a high quality standard. Importantly, patients have the possibility to stay at their regional hospitals, where they are treated by their local oncologists and remain within their social environments. Prof. Dr. Richard Herrmann, Basel Correspondence: Annik Steiner Head Partner Relations SAKK-Koordinationszentrum Effingerstrasse 40 CH-3008 Bern Phone +41 (0)31 389 93 96 Fax +41 (0)31 389 92 00 annik.steiner@sakk.ch

Hess Christoph Innate immunity, cytokine polymorphisms, and development of post-transplant lymphoproliferative disease in kidney transplant recipients (OCS 2266-08-2008) After transplantation of solid organs, patients must undergo lifelong pharmacological immunosuppression to prevent rejection of the transplant. Post-transplant lymphoproliferative disorders (PTLDs), i. e. lymphomas arising in patients under immunosuppressive therapy, are a rare yet severe complication after transplantation. Prior to PTLD development, most patients experience Epstein- Barr virus (EBV) re-activation or de novo infection. Due to lack of immunological control of EBV, this usually benign infection can mediate lymphomagenesis in immunosuppressed patients. Several potential risk factors for PTLD development have previously been studied. It is known that the incidence of PTLD rises with increasing intensity of the immunosuppressive regimen applied. Transplantation of an EBV-positive organ into a patient that has previously not been infected with EBV also represents an important risk factor. In small series of patients the potential impact of various components of the immune system on PTLD development was analyzed. Results of these analyses have remained controversial, as several associations could not be confirmed in other cohorts of patients. In conjunction with the Collaborative Transplant Study (University of Heidelberg, Germany), we therefore analyzed a very large cohort of patients developing PTLD after transplantation. The aim of this investigation was to determine possible risk factors in the development of PTLD, as well as factors that influence the course of this disease once it is established. We analyzed 236 patients using genotyping. We were particularly interested in factors influencing the immune system and polymorphisms in genes that are important in the development of inflammatory responses. We showed that none of the genetic polymorphisms that code for proteins important in the inflammatory response (specifically interferon alpha, transforming growth factor beta and interleukin 10) have any influence on the development of PTLD or on the course of this disease. This contradicts previous studies, which, however, had included only a few dozen patients at most. The factors influencing the innate immune system that were analyzed in parallel also did not predict which patients were at risk for PTLD development. However, two polymorphisms in genes that code for proteins expressed on the surface of natural killer cells (KIR2DL2/3 and FcgRIIIa) were found to have a strong influence on the survival of patients that had developed PTLD. Natural killer cells are a subgroup of lymphocytes that are important in the defence against tumours and viral infection. The results of our investigation indicate that none of the investigated factors can help to identify which patients are at particularly high risk for PTLD development. This stands in clear contrast to previous smaller studies. Future studies will have to determine whether the polymorphisms identified to determine the course of established PTLD will have an impact on the treatment of this disease. Prof. Dr. Christoph Hess Ambulante Innere Medizin Medizinische Poliklinik Universitätsspital Basel Petersgraben 4 CH-4031 Basel Phone +41(0)61 265 44 75 Fax +41(0)61 265 43 00 chess@uhbs.ch Hess Viviane Improving treatment for patients with advanced pancreatic cancer (APC): A Swiss-wide effort (KLS 01881-04-2006) Pancreatic cancer is the fifth leading cause of cancer deaths in the Western world, and incidence is increasing. Furthermore, the vast majority of patients are diagnosed with advanced, incurable disease with a median survival time of four to eight months. Our clinical research projects all aim at improving treatment options for these patients. Methods We conducted three multicentre clinical studies focusing on 1) translational, 2) therapeutic, and 3) Swiss-specific epidemiological aspects. Results 1) The serum tumour marker CA 19-9 is elevated in most patients with pancreatic cancer, and measuring its changes during therapy would represent an ideal way of judging treatment efficacy (surrogate marker). Surprisingly, however, in our large prospective cohort of patients, we found that a decrease of the CA 19-9 serum concentration during chemotherapy was not associated with lengthened survival regardless of whether a 25 %, 50 % or 75 % decrease was examined. 2) Combining the three most efficient drugs in pancreatic cancer gemcitabine, oxaliplatin and capecitabine (GEMOXEL) was well tolerated at the recommended dose (determined through inter-patient dose escalation) and showed a decrease in tumour volume in 41 % of patients in our multicenter prospective setting. The percentage of patients with substantial tumour shrinkage by far met the pre-defined criteria for further investigating this triple combination and makes it particularly interesting in the pre-operative setting. 3) Between 2001 and 2004, six large Swiss centres actively recruited patients with advanced pancreatic cancer for a therapeutic trial. Yet, during this period, only 23 % (out of a total of 275 patients) were treated on protocol. The majority (88 %) of patients treated outside of a study setting were in a medical condition allowing for chemotherapy treatment. Therefore, study participation was hindered by factors other than medical condition. Survival times for patients treated on or off study protocols did not differ statistically. 137

138 Conclusions A strong network of committed centres throughout Switzerland has been built allowing work towards the progress so desperately needed in this disease setting. Given that only one out of five patients is treated on a trial protocol, there is a huge potential for further increasing clinical research activities. The triple combination therapy GEMOXEL is well tolerated, and given the large percentage of patients experiencing tumour shrinkages, further investigation in the preoperative setting is warranted. Decrease of the serum tumour marker CA 19-9 during chemotherapy is not a surrogate marker for survival. This finding has major implications for future study design. This project was awarded the 2009 Pfizer Research Award. PD Dr. Viviane Hess Medizinische Onkologie Universitätsspital Basel Petersgraben 4 CH-4031 Basel Phone +41 (0)61 265 50 59 vhess@uhbs.ch Hunger Robert E. Malignant melanoma: Correlation of dendritic cell (DC) and T-cell markers with prognosis (OCS 02262-08-2008) In patients with malignant melanoma the most important parameters for prognosis are tumour thickness according to Breslow, ulceration of the primary tumour and sentinel lymph node status. However, sentinel lymph node dissection to determine nodal status of the patient is costly and requires surgery. The aim of this study was to find markers to assess the risk to form metastasis that do not require surgery. To this end we immunohistochemically stained semiserial tissue sections of 200 primary melanoma with monoclonal antibodies for the dendritic cell related markers CD1a, DC-LAMP, langerin, BDCA-2 and the T-cell markers granzyme B, TIA and FOXP3. Marker expression was assessed for all samples by counting positive cells under a microscope and by a digitalized image analysis system. The results of both counting systems revealed similar results with a highly significant correlation coefficient. In primary melanoma with positive sentinel lymph node we found a higher expression of the markers BDCA-2 and DC-LAMP compared to tumours with negative sentinel lymph nodes. Further analysis, especially the assessment of the T-cell related markers and the analysis of both sets of markers, will hopefully provide more prognostic information for patients with melanoma by just analyzing the primary tumour. Prof. Dr. Robert Hunger Universitätsklinik für Dermatologie Inselspital CH-3010 Bern Phone +41 (0)31 632 2613 robert.hunger@insel.ch Imhof Beat A. The mechanism of anti-jam-c antibodies blocking tumor angiogenesis (OCS 01653-02-2005) For several years, our laboratory, which specializes in studies of regulatory proteins in vascular physiology, has been searching for novel actors implicated in tumour angiogenesis. Angiogenesis is characterized by the formation of new blood vessels that sprout from the existing vasculature. This mechanism is essential for tumour growth and development, as the newly formed vessels provide oxygen and nutrients to tumour cells. For this reason, it is important to understand and thereby inhibit the molecular mechanisms involved in the formation of new blood vessels, so as to starve the tumours and halt their development. Our laboratory previously discovered JAM- C, a novel molecule that is involved in tight junctions between endothelial cells and controls permeability of vessels. By blocking JAM-C during angiogenesis with monoclonal antibodies, we were able to block the formation of new blood vessels in the developing retina of mice and in aortic cultures in vitro. During discussions with Prof. Pierre-Yves Dietrich, head of oncology at University Hospital of Geneva, we decided to test whether our anti-jam-c antibodies could inhibit the growth of glioblastoma and their fatal invasion into the brain. These tumours are particularly aggressive, and current treatments are not very effective in preventing tumour progression. We first used a mouse glioblastoma cell line and implanted these cells into the brain of mice. Tumour progression and invasion were imaged in vivo by magnetic resonance image technology. Treatment of these mice with anti-jam-c antibodies reduced the size and spreading of glioblastoma tumour in the brain. Closer analysis revealed that the antibody reduced the vascular density but also affected the tumour itself, as glioblastoma cells also expressed JAM-C. This was surprising, for normal glial cells do not express JAM-C. We then investigated whether JAM-C would regulate the expression of genes in tumour cells and found several candidate genes whose expression was upregulated with potential roles in cell migration and invasion. In conclusion, JAM-C is a molecule involved in the angiogenic development of blood vessels and the regulation of invasive migration of tumour cells, in particular glioblastoma. In the long term, we plan to use humanized anti- JAM-C antibodies as a novel targeted weapon for anticancer treatment. Prof. Dr Beat A. Imhof Département de pathologie et immunologie Faculté de médecine Centre médical universitaire (CMU) Université de Genève Rue Michel-Servet 1 CH-1211 Genève Phone +41 (0)22 379 57 47 Fax +41 (0)22 379 57 46 beat.imhof@unige.ch

Irminger-Finger Irmgard BRCA1-associated protein, BARD1, a molecular target for breast cancer screening and cancer therapy (KLS 01962-10-2006) Breast cancer is the most frequently diagnosed cancer in the Western world, and the numbers are increasing in the emerging economies, such as China, India and Brazil. It is assumed that this latter increase is due to a change in nutritional lifestyle and might be explained by the increased consumption of oestrogens through the food chain. Oestrogens act through the oestrogen receptor alpha (ER-alpha), which induces the transcription and upregulation of a variety of target genes, among which are the breast cancer genes BRCA1 and BRCA1-associated RING domain protein 1 (BARD1). BARD1 is often described as a protein binding to BRCA1. It acts as stabilizer of BRCA1 and enhancer of the E3 ubiquitin ligase activity of BRCA1, which is important for controlled turnover of many target proteins, and one of these is ER-alpha. However, BARD1 isoforms that lack the BRCA1-interaction domain are upregulated in breast and ovarian cancer, and their expression is correlated with poor prognostic factors, such as tumour size, stage and grade. Thus BARD1 isoforms are biomarkers of cancer progression. The overall goal of our project was: 1) to characterize the oncogenic functions of breast cancer-specific BARD1 isoforms and generate tools for their inhibition; and 2) to develop methods for their detection in the blood. To reach these goals we cloned individual isoforms in expression vectors, expressed them in breast cancer cell lines and generated antibodies against epitopes specifically expressed on BARD1 isoforms. With this approach we could demonstrate that BARD1 isoform delta acts antagonistically to the function of the BRCA1-BARD1 E3 ubiquitin ligase in the controlled degradation of the ER-alpha. We also demonstrated that overexpression of BARD1-delta leads to ER-alpha accumulation, as it is observed by repression of full length BARD1 or BRCA1. Importantly, ERalpha induces expression of BARD1 but also BARD1 isoforms when activated by oestrogen, which leads to a feedback loop of increased expression of isoforms. Since oestrogen is the biggest risk factor for breast cancer, inhibition of ER-alpha upregulation, based on the inhibition of BARD1 delta, could be an important novel tool for targeted cancer therapy. We also showed that expression of isoform beta antagonizes the degradation of the mitotic kinase Aurora B, while the turnover of Aurora B is normally regulated by BRCA1- BARD1 E3 ubiquitin ligase. Inhibition of Aurora B expression or activity is important for controlling the proliferation of tumour cells. Repression of BARD1-beta by small interfering RNA (sirna) leads to growth arrest in several cancer cell lines tested in vitro. Thus, inhibiting BARD1- beta isoform expression can be exploited for the development of a novel targeted cancer therapy. To demonstrate that BARD1 isoforms could be detected in the blood, we used sera from breast cancer patients and performed enzyme-linked immunosorbent assay (ELISA) using antibodies specifically recognizing BARD1 isoforms to detect them in sera from patients with breast cancer. Further work will be necessary to clearly prove whether BARD1 isoform detection in the patient s blood can be used as diagnostic tool. Dr Irmgard Irminger-Finger Laboratoire de gynécologie-obstétrique moléculaire Département de gynécologie et d obstétrique Maternité Hôpitaux universitaires de Genève (HUG) Boulevard de la Cluse 30 CH-1211 Genève Phone +41 (0)22 382 43 27 irmgard.irminger@unige.ch Kalberer Christian P. Role of NKG2D receptor-ligand interactions in the recognition of human B-cell neoplasms by natural killer cells (OCS-01870-02-2006) Human natural killer (NK) cells are important effectors of the innate immune system and contribute to the first line of defence against virus-infected cells and tumour cells. Cognate interactions of activating NK cell receptors and their ligands result in target cell killing. The activating receptor NKG2D recognizes ligands that, in humans, belong to the ULBP and MIC gene families and are crucial determinants in anti-tumour immunity. Our recent studies in patients with acute myeloid leukaemia showed that malignant cells express low levels of ULBP and MIC ligands, resulting in evasion of leukaemic blasts from immune surveillance by NK cells. This study addresses the molecular mechanisms regulating ULBP1 leading to low surface expression levels in acute leukaemias. The goal was to investigate the role of the 3 untranslated region (3 UTR) in post-transcriptional regulation of ULBP1 expression. Considerable differences in length and sequence of the 3 UTRs of the ULBP genes suggest that this region plays a role in differential expression of ULBPs. Indeed, sequence analysis of 2.4 kb-long ULBP1-3 UTR revealed potential binding sites for more than 200 micro- RNAs and the presence of four AU-rich elements (ARE), the regulatory components of RNA degradation and translational suppression. Stable or transient delivery of luciferase reporter constructs containing the full-length ULBP1-3 UTR sequence with lentiviral vectors or expression plasmids resulted in a strong reduction of luciferase activity to 7 22 % in Jurkat, HeLa cells and human primary fibroblasts, indicating a contribution of 3 UTR to the regulation of ULBP1 gene expression. To determine the position of regulatory sequences in the ULBP1-3 UTR, we generated nine vectors carrying different fragments of ULBP1-3 UTR that all led to significant reductions of luciferase activity to 19 62 %. The suppressive effects were seen with every fragment along the 3 UTR, suggesting that the regulatory sequences are distributed over the entire 3 UTR rather than restricted to specific areas. Muta- 139

140 tions introduced to ARE motifs significantly diminished luciferase activity, suggesting an mrna stabilizing effect of ARE. Among ULBP1-specific candidate micrornas, we found mir-140-5p/-409-3p/-433-3p/-650 expressed in HeLa and Jurkat cells, and the microrna involvement was supported by luciferase reporter assays with constructs carrying seed sequence mutations. However, microrna overexpression or partial silencing of the microrna processing enzyme Drosha did not equivocally clarify the role of micrornas in regulation of ULBP1. Altogether, these results provide evidence for a novel 3 UTR-mediated mechanism of regulation of ULBP1 at the post-transcriptional level. Given that NKG2D ligand expression is crucial for tumour recognition, targeting 3 UTR of ULBP1 may represent a tool to upregulate tumour-associated ligands for the activating immunoreceptor NKG2D. Revealing the different gene expression mechanisms will open up important new therapeutic outlooks by modulating ligand levels, which will potentiate the effect of NK cell immunotherapy against leukaemias. PD Dr. Christian Kalberer Diagnostische Hämatologie Labormedizin Universitätsspital Basel Petersgraben 4 CH-4031 Basel Phone +41 (0)61 265 25 25 Fax +41 (0)61 265 44 50 ckalberer@uhbs.ch Kalia Yogeshvar N. Non-invasive transdermal iontophoretic delivery of antiemetic drugs for the treatment of chemotherapy-induced nausea and vomiting (OCS 01753-08-2005) Chemotherapy-induced nausea and vomiting (CINV) affects 70 80 % of cancer patients. Two distinct phenomena have been reported, acute and delayed emesis. Intravenous (IV) administration of antiemetics is effective in treating acute emesis; however, it is less practical for the treatment of delayed emesis. Oral administration is more convenient but poses problems for patients suffering from emesis and prone to vomiting. Diarrhoea, malabsorption, gastrointestinal ulceration and the occurrence of oral mucositis can also severely reduce oral bioavailability. There is a need to develop non-invasive methods for the controlled delivery of antiemetics that can improve their efficacy against delayed emesis. Dosing can be problematic, particularly in children; the ideal delivery system should function as a needle-free pump, providing tight control over drug input without the invasiveness of an IV infusion. Transdermal delivery is convenient and the ease-of-use of modern patches means they are well-accepted by the public. However, the skin s excellent barrier function restricts drug delivery into the body and limits the number of drugs that can be delivered by this route. Iontophoresis uses a small electric current to enable the controlled delivery of molecules that cannot otherwise overcome the skin barrier. The amount of drug delivered (or the dose) depends directly on the intensity and duration of current application. The long-term goal of our research is to develop an efficacious alternative to the oral and IV administration of antiemetics and to improve the quality of life of patients with cancer. Purpose The aim of the project was to evaluate the feasibility of using transdermal iontophoresis for the controlled non-invasive delivery of antiemetics used in the treatment of CINV; in particular with a view to developing more patient-friendly treatment options for delayed emesis. Method The first part of the study investigated the iontophoretic delivery of the different therapeutic agents granisetron (GST), metoclopramide (MCP) and dexamethasone sodium phosphate (DEX) singly. Then, since the complex aetiology of CINV has resulted in the co-administration of drugs that target the different receptors responsible for stimulating the emetic centre within the brain, we investigated the co-iontophoresis (that is, simultaneous delivery) of these agents. Results Initial experiments demonstrated the feasibility of delivering therapeutic amounts of each of the antiemetic agents, GST, MCP and DEX across the skin. This was also the case for the co-iontophoresis studies i. e. the experiments involving simultaneous administration of multiple agents (GST, MCP and DEX). Preclinical animal studies were also successful. The project provided the first demonstration of the feasibility of administering a polytherapy by using transdermal iontophoresis. Potential benefits for patients The results confirmed the potential of iontophoretic systems to deliver the antiemetics used to treat CINV. During the course of this project, the first conventional transdermal patch for granisetron was launched highlighting the utility of this route for treating CINV. However, iontophoretic patch systems would be smaller and provide faster symptom relief. In the future, we intend to investigate the transdermal delivery of newer, more potent antiemetics and to develop an effective alternative to their administration by the oral and IV routes. Dr Yogeshvar N. Kalia Section des sciences pharmaceutiques (Ecole de pharmacie Genève Lausanne) Université de Genève Quai Ernest-Ansermet 30 CH-1211 Genève 4 Phone +41 (0)22 379 33 55 Fax +41 (0)22 379 33 60 yogi.kalia@unige.ch

Maiwald-Urosevic Mirjana Role of versican in the biology of Sézary cells (OCS 01934-08-2006) Sézary syndrome (SS) belongs to cutaneous lymphomas, a heterogeneous group of lymphatic malignancies characterized by red and scaly skin, lymph node enlargement and the presence of atypical tumour lymphocytes, called Sézary cells (SCs) in peripheral blood. In contrast to other skin lymphomas with a T-cell phenotype, SS has an unfavourable prognosis. The exact mechanisms underlying accumulation of malignant SCs in the skin and/or enabling their circulation in peripheral blood are still poorly defined. Accordingly, the various treatments for SS are generally disappointing, reflecting the need for new targets. SCs appear to lack regulatory activity governing their response to chemokines, which might potentate their homing to the skin. By using high-throughput gene expression profiling of SCs obtained from peripheral blood of patients, we could identify a highly overexpressed gene, termed versican. Versican is one of the major components of the extracellular matrix and is able to bind various chemokines, thus influencing the cellular response to chemokines and changing the migratory behaviour of lymphoid cells. Moreover, overexpression of versican (or its different isoforms) appears to be responsible for the changes in the susceptibility of tumour cells to apoptosis. The results obtained in this project provide new information that can be used in the development of treatment strategies targeting migratory behaviour of lymphoid tumour cells. This could be of importance not only in skin lymphomas but also in other T-cell malignancies with possible blood involvement. PD Dr. Mirjana Maiwald-Urosevic Dermatologische Klinik UniversitätsSpital Zürich Gloriastrasse 31 CH-8091 Zürich Phone +41 (0)44 255 11 11 mirjana.maiwald@usz.ch Matthes Thomas Analysis of transcription factors PU.1 and GATA-1 functions in myelodysplastic syndromes, in acute myeloid leukemia and in leukemia stem cells (OCS 01781-08-2005) Transcription factors are intracytoplasmic proteins that regulate the normal cell differentiation from undifferentiated omnipotent stem cells to fully mature end-differentiated cells with specialized functions in different organs. In the haematopoietic system, they orchestrate the differentiation into the various different red and white blood cells that circulate in the peripheral blood and populate the various lymphoid organs of the body. They also play a role in acute myeloid leukaemia (AML), in which this normal differentiation program is blocked, as well as in myelodysplastic syndromes (MDS), preleukaemic states in which transcription factor expression is dysregulated. Aim To study the function of two particular transcription factors, PU.1, the key regulator of myelopoiesis, and GATA-1, the key regulator of erythropoiesis, in normal haematopoietic differentiation, in AML and in MDS. Methods We used lentivectors, which code for PU.1 or GATA-1, to transduce normal stem cells, primary blast cells from patients with AML, and AML cell lines, and from patients with MDS. In in vitro cultures we analyzed the effect of overexpressed PU.1 or GATA-1 on the differentiation and proliferation potential of the transduced cells, on their phenotype and on their resistance to apoptotic stimuli. Results Transduction of cells with the two lentivectors led to overexpression of mrna and protein of the corresponding transcription factors. After several days of culture, blasts transduced with PU.1 showed myelomonocytic differentiation and phenotypic changes compatible with restored blast differentiation. These effects were similar to the effects observed by adding all-trans retinoic acid (ATRA) to the cell cultures, a treatment currently used in the clinics in a subtype of AML. At later time points cells showed morphologic changes typical of macrophages, and increased apoptosis, characteristic of end-differentiated cells. The observed effects were dose-dependent and occurred only when PU.1 levels were above a certain threshold. Blast cells transduced with GATA-1 did not show any of the effects observed in PU.1 transduced cells, although GATA-1 protein levels were increased. Conclusion Our results show that artificially induced changes in transcription factor levels can influence the destiny of leukaemic blast cells by overcoming the differentiation block typical of these cells and restoring their normal differentiation program. Targeting PU.1 or one of the other known molecules in the PU.1 signal transduction pathway in AML could therefore constitute an interesting alternative approach for the treatment of this still incurable disease. Dr Thomas Matthes Service d hématologie Département de médicine interne Hôpitaux universitaires de Genève (HUG) 6, rue Gabrielle-Perret-Gentil CH-1211 Genève 4 Phone +41 (0)21 372 39 30 Fax +41 (0)21 372 72 88 thomas.matthes@hcuge.ch 141

142 Müller Beatrice U. The master transcription factor PU.1 is essential for normal hematopoiesis: Analysis of PU.1 alterations in patients with acute myeloid leukemia (AML) (OCS 1731-08-2005) The majority of patients with acute myeloid leukaemia (AML) still die of the disease, and novel therapeutic concepts are needed. In leukaemic cells, the normal development of white blood cells is typically blocked at a particular stage, and blocked differentiation is, in fact, the hallmark of acute leukaemia. Timely regulation of the key transcription factor PU.1 is crucial for normal haematopoiesis. We previously showed that PU.1 expression is specifically suppressed in patients with AML-M3. In addition, targeted disruption of an upstream regulatory element (URE) located 15 kb upstream in the PU.1 promoter was reported to decrease PU.1 expression by 80 % and lead to AML in mice. Here, we screened patients with AML for mutations in the entire URE sequences of PU.1. We detected two polymorphisms in 4 out of 120 patients with AML (3.3 %) and in 1 out of 141 healthy volunteers (0.7 %). Both polymorphisms were localized in the distal homology region (DHR) of the URE within 10 bp affecting a putative NF-kB site. We found that NF-kB p50/p65 heterodimers and p50/p50 homodimers were indeed binding to this site and that NF-kB p50/ p65 activated PU.1 expression through this site in the URE. Remarkably, NF-kB mediated activation was abolished by the polymorphisms detected in patients with AML. Further, NF-kB synergistically activated PU.1 together with CEBPB, whereas this synergy was lost in the presence of these polymorphisms. Finally, patients with AML with the polymorphic NF-kB sequence showed suppressed PU.1 mrna expression. Our results demonstrate that NF-kB mediated activation of PU.1 is deregulated by polymorphisms in the URE of PU.1, which are more frequent in patients with AML than in healthy individuals. Moreover, our study suggests that an insertion of even only a single base pair in a distal element critically affects the regulation of a tumour suppressor gene and thus contributes to the development of cancer. Dr. Beatrice U. Müller Departement für allgemeine Innere Medizin und klinische Forschung Inselspital CH-3010 Bern Phone +41 (0)31 632 03 78 Fax +41 (0)31 632 0514 beatrice.mueller@insel.ch Perrier Patrick Impact of UV light on melanoma development (OCS 01911-08-2006) Incidence of cutaneous melanoma is constantly increasing in our latitudes in fair-skinned individuals. The principal aim of our project was to try to dissect some of the effects of UV light leading to development of melanoma. To do so, we started from a postulate formulated in 1995 by Tronnier and colleagues. This group showed that UV irradiation of benign nevi was able to reversibly simulate in situ malignant melanoma by promoting pagetoid migration of melanocytes towards superficial epidermal layers. They showed that melanocytes were activated and expressed higher levels of HMB-45. After 3 weeks, however, the initial morphological aspect of the nevus could be seen again, without any sign of melanocytic atypia. Tronnier et al. s observations could be reproduced in our laboratory 7 days after irradiation of human normal nevi by both UVA and UVB. The interplay between melanocytes and keratinocytes in response to UV is probably based, at least in part, on the production of immune mediators. We are currently exploring the expression of several inflammatory and angiogenic factors. On the other hand, chemokines and chemokine receptors are under study for their expression in keratinocytes and melanocytes, respectively. Besides their role in orchestrating leukocyte trafficking, chemokines have been described for their capacity to participate in driving organ-specific metastasis from primary tumours. A. Muller et al. were among the first active in this field and were subsequently followed by many others who demonstrated the capacity of these molecules to induce primary tumoural cells to migrate. Several groups then studied the expression of these chemokines in primary melanomas, in lymph node and organ metastasis and in melanocytic lesions; expression differs for each histological setting. So far, to our knowledge, little work has been done on chemokine/chemokine receptor expression by keratinocytes and melanocytes in response to UV light, and this is our next point of interest. Our project is still underway. The description of the complex interplay between melanocytes and keratinocytes is necessary to better understand the first steps of melanoma development. Dr Patrick Perrier Service de dermatologie Département de médecine Centre hospitalier universitaire vaudois (CHUV) CH-1011 Lausanne Phone +41 (0)79 556 58 36 Patrick.Perrier@chuv.ch

Renevey Philippe Development of a voice restoration system for laryngectomees in order to improve their social interaction (OCS 01777-08-2005) Laryngectomy denotes a treatment of laryngeal cancer requiring partial or total removal of the larynx. The loss of the vocal function is one of the very distressing consequences of this pathology. Medical rehabilitation techniques allow laryngectomees to partially recover vocal function, but it results in poor voice quality and insufficient speech intensity. The main goal of this project was to develop speech signal processing methods for the restoration of the voice quality in laryngectomees speech. In particular, the proposed scheme estimates parameters from the pathological speech and uses a voice model to restore missing or degraded voice characteristics. The naturalness and emotional paralinguistic features found in healthy voices are restored from different cues estimated from the pathological voice. Healthy speech is then reconstructed by recombining the previously estimated speech parameters and the new voice source. The procedure adopted for this project was initially based on the enhancement and adaptation of existing speech signal processing algorithms to the particular characteristics of pathological speech. The first results indicated that the investigated methodologies needed further development and innovation in order to obtain satisfactory results. The following aspects have been investigated: The parameter estimation has focused mainly on a reliable estimation of rudimentary variations of the fundamental frequency and of the articulation parameters. After evaluation of state-of-the-art methods, a novel method called adaptive wavetable oscillator was developed; it provides a good theoretical match to the revealed problems with pathological voice excitation. This new method exhibits reduced computational costs and provides similar performance to state-of-the-art methods. For the estimation of the articulation parameters, a method based on sub-space projection was developed, but it led to unsatisfactory results. Alternatively, a sub-band approach was developed, which led to increased estimation results but requires a dedicated method for the reconstruction of the speech signal.

144 A novel method was developed for the reconstruction of a voice with more natural fundamental frequency and increased voice quality. It became obvious that the variability in the fundamental frequency may not be sufficient to restore prosody. This finding led to the development of a multi-resolution approach, where voluntary variations in the voice are restored based on different vocal cues on different time scales. The algorithmic solutions developed in the framework of the project represent a significant step in the understanding and processing of pathological voices. However, the results obtained also highlighted the difficulty and complexity of the restoration process. The actual restoration results are not yet sufficient to be integrated in a device aiming at improving the quality of life of laryngectomees (vocal aid, improvement of telephone calls, public audience amplification, etc.), but the research work is still underway. Dr Philippe Renevey Centre suisse d électronique et de microtechnique (CSEM) Rue Jaquet-Droz 1 CH-2007 Neuchâtel Phone +41 (0)32 720 55 27 prv@csem.ch which is mainly composed of very specific kinase inhibitors that allow targeting of specific signalling pathways. Using Ewing s sarcoma cells, we identified drugs targeting the PI3K/mTOR pathway as being the most effective. Strikingly, rhabdomyosarcoma cell did not react that well on this group of inhibitors but was most sensitive to drugs targeting components of the cell cycle. We found that an important cell cycle kinase is directly involved in stabilizing the fusion protein. Both drugs are now being further evaluated for anti-tumourigenic activity in an in vivo mouse model. The results of this project represent the first step towards improvement of current therapies for sarcomas by inhibiting the activity of the fusion proteins lying at the centre of tumourigenicity. These drugs now need to be further developed in pre-clinical models. Prof. Dr. Beat W. Schäfer Abteilung Onkologie Kinderspital Zürich Universitäts-Kinderkliniken Steinwiesstrasse 75 CH-8032 Zürich Phone +41 (0)44 266 75 53 Phone +41 (0)44 634 88 52 beat.schaefer@kispi.uzh.ch Schäfer Beat W. Oncogenic fusion proteins as therapeutic targets in pediatric sarcomas (OCS 02264-08-2008) Childhood sarcomas are aggressive tumour entities. This is especially true of the type of sarcomas that are characterized by the presence of a chromosomal translocation and include rhabdomyosarcoma and Ewing s sarcoma. Several previous studies from different laboratories demonstrated that the fusion proteins produced by chromosomal translocations are important for both tumour development and tumour cell survival. Therefore, these oncogenic transcription factors represent important target molecules for the development of novel treatment strategies. Unfortunately, this development is challenging due to the nature of the proteins involved, and for this reason it is not actively pursued by industry. The aim of the current project was therefore to develop a method by which the activity of these fusion proteins can be measured and subsequently inhibited by small-molecule chemical compounds. The method developed for this relies on measuring transcriptional activity based on a few carefully selected target genes. We successfully implemented and validated such a method. Next, we screened a library composed of small-molecule chemical compounds and a library composed of the latest drugs under development in oncology. Interestingly, we first identified a novel drug called fenretinide, a retinoic acid analogue that is now under development for Ewing s sarcoma and neuroblastoma, as also being effective for rhabdomyosarcoma. Equally interesting were results from the second library, Schäfer Beat W. Prognostic classification of rhabdomyosarcoma: A combined retro- and prospective study (OCS 1944-08-2006) Childhood sarcomas are aggressive tumour entities. When metastatic, these tumours often have a fatal course despite aggressive treatment with chemo- and radiotherapy. Therefore, there is an urgent need to improve therapy in this tumour group. The most frequently occurring sarcoma in childhood and adolescence is rhabdomyosarcoma. The aim of our study was to simplify pathological classification into different rhabdomyosarcoma subgroups that are based on biological criteria. Historically, subgroup classification is based on histological analysis and divides rhabdomyosarcoma into tumours with embryonal and alveolar histology. Biological analysis in the past also revealed two subgroups: One subgroup is characterized by the presence of a specific genetic aberration, a chromosomal translocation that is lacking in the other subgroup. These two genetic groups only partially overlap with the ones based on histology. However, identification of this genetic aberration is crucial, since treatment and prognosis depend by and large on its presence. Whereas genetic methods are clearly able to identify the aberration, applying those methods can be sophisticated. To improve recognition of the genetic aberration, we therefore searched for biomarkers that would be indicative on simple histological sections. In our previous work, we could indeed identify four biomarkers based on gene expression profiles that fulfilled all criteria necessary. In the present project, we have now validated these markers on a large cohort of patients with rhabdomyosarcoma in collaboration with the German Cooperative Soft Tissue

Sar coma study (CWS study) (chaired by Prof. E. Koscielniak, Stuttgart, and Prof. T. Klingebiel, Frankfurt). We indeed confirmed differential expression of these markers in the genetic subgroups. Expression of the markers therefore also correlated with overall survival of the patients. The biomarkers identified in this study have now been incorporated into the clinical risk stratification. Hence, our study made a substantial contribution to improved diagnostics of patients with rhabdomyosarcoma. Prof. Dr. Beat W. Schäfer Abteilung Onkologie Kinderspital Zürich Universitäts-Kinderkliniken Steinwiesstrasse 75 CH-8032 Zürich Phone +41 (0)44 266 75 53 Phone +41 (0)44 634 88 52 beat.schaefer@kispi.uzh.ch Speiser Daniel E. Analysis of key mechanisms of human melanoma specific CD8 + T cell responses: Long term persisting clonotypes and strong effector functions (OCS-01917-08-2006) Immunotherapy can enhance the capacity of the immune system to protect the body against cancer. Our aims are to optimize this type of therapy for patients with cancer towards increased clinical efficacy. During this development, we identify key properties of human immune cells (T cells) that are associated with protective immunity. After vaccination of patients with melanoma with tumour antigenic peptides, CpG and Incomplete Freund s Adjuvant (IFA), peptide-specific T cells expanded rapidly and reached high frequencies and reached on average > 1 % of CD8 T cells in peripheral blood. Our analysis revealed considerable tumour-specific cytolytic function and cytokine production by these T cells. This represents the first direct ex vivo demonstration of human cancer-specific multifunctional T cells that readily produced multiple cytokines (IFNg, TNFa and IL-2) and upregulated LAMP-1 (CD107a) correlating with strong lytic activity. Interestingly, these responses were independent of patient age and gender, suggesting that elderly patients can also benefit from immunotherapy. Multiple subsequent monthly booster vaccinations promoted progressive differentiation to (CD28 negative) effector T cells with enhanced function. T cell receptor (TCR) and T cell clonotype analysis revealed that these T cells persisted over several years. The clinical responses were mixed, with about half of the patients that remained tumour free or progression free. In some patients, however, we observed progression of tumours, in part due to immune escape, i. e. by progression of antigen- or HLA-loss variant tumours. Fortunately, this immune escape was slow (on average only after several years). Together, our study shows for the first time that a cancer vaccine can induce multifunctional and thus immune competent tumour-specific T cells. Therefore, the data fully support further development of this approach, particularly by vaccinating with multiple tumour-antigens, which presumably minimizes the risk for immune escape. A few years ago, monitoring of T cell responses was limited to techniques based on the detection of antigen-specific T cells using tetramers and analysis of their function essentially by the assessment of cytokine production such as Interferon-g. However, these techniques have limitations, because they fail to determine major correlates of T cell mediated protection. Therefore, we developed additional strategies. Although labour intensive, our new techniques allow the assessment of T cell precursor frequency, T cell affinity / avidity, molecular and functional TCR properties and extended gene profiling of tumour-specific T cells. Our novel techniques combining tetramers with functional analysis allowed elucidation of key signalling mechanisms in tumour-specific T cells. Further, we investigated the roles of inhibitory receptors (e. g. PD-1, CTLA-4, BTLA) in functional T cell deficiency. We found that the latter is particularly important in metastases. Our strategy of functional analysis directly ex vivo of blood-derived T cells, and also of T cells from tumour tissue of patients with cancer, is well suited to evaluate the biological efficacy of available cancer therapies. Comprehensive characterization of biological and medical effects of novel therapies provides the basis for overall improvement of cancer therapy but also for better care of individual patients. Prof. Dr. Daniel E. Speiser Ludwig Institut für Krebsforschung Universitätsspital Lausanne HO 05/1552 Avenue Pierre-Decker 4 CH-1011 Lausanne Phone +41 (0)21 314 01 82 daniel.speiser@hospvd.ch Taverna Christian Comparing two schedules of rituximab maintenance in rituximab-responding patients with untreated, chemotherapy resistant or relapsed follicular lymphoma: A randomized phase III trial of the SAKK (Swiss Group for Clinical Cancer Research) (OCS 02125-08-2007) Malignant lymphomas are malignancies that arise in the lymph nodes or in the lymphatic system. Follicular lymphoma is the second most common non-hodgkin s lymphoma. It is an indolent, i. e. non aggressive, malignant lymphoma. At the time of diagnosis the median age is about 60 years, and patients are often in an advanced stage of disease. Patients with follicular lymphoma usually have a slowly progressive course, and there are cases with stable disease for years without any treatment. Despite good response to systemic treatment, there is a high incidence of relapse. A cure can be attained in rare cases. The median overall survival is 10 years. The monoclonal antibody rituximab, which binds to the cell surface antigen CD 20, has remarkably improved treatment results. Rituximab is effective as a single agent as well as in combination with conventional chemotherapy. The side effect profile of the monoclonal antibody differs from the side effects of conventional chemotherapeutic agents. Different strategies have been evaluated to minimize the high relapse rate in follicular lymphoma. In a previous trial 145

146 (SAKK 35-98) the Swiss Group for Clinical Cancer Research (SAKK) showed that maintenance treatment with rituximab four times every two months significantly improved event-free survival. Rituximab is usually well tolerated and is well suitable for maintenance treatment. The optimal duration of maintenance therapy is unknown. The current study is investigating whether prolongation of the maintenance therapy leads to improved results. Patients with newly diagnosed, chemotherapy resistant or recurrent follicular lymphoma were included in this trial. After an induction therapy of four weekly infusions of rituximab, patients with partial or complete remission were randomised to a short maintenance or a prolonged maintenance for a maximum of five years or until progression or unacceptable toxicity. Primary endpoint is eventfree survival. Secondary endpoints are progression-free survival, overall survival, response rate, toxicity, molecular remission, duration of molecular remission and evolution of immunologic competence. Molecular analyses were performed by Dr. Francesco Bertoni (Experimental Oncology, Oncology Institute of Southern Switzerland, Bellinzona). From October 2004 to November 2007, 270 patients from 24 centres in seven countries were included and received induction treatment with rituximab. Many patients are still under trial treatment, and therefore an efficacy analysis has not yet been performed. Two safety analyses showed that rituximab maintenance therapy beyond two years is safe. Dr. Christian Taverna Onkologie Medizinische Klinik Kantonsspital Münsterlingen CH-8596 Münsterlingen Phone +41 (0)71 686 22 02 Fax +41 (0)71 686 26 51 christian.taverna@stgag.ch Terracciano Luigi M. HOXA13 hyper-expression in liver cancer: A potential node toward angiogenesis (OCS 02005-02-2007) HOX genes control normal development and primary cellular processes and are characterized by a unique genomic network organization. The comparison of the HOX gene network expression between nontumourous livers and hepatocellular carcinomas highlights significant differences in the expression of locus A HOX genes with a consistent over-expression of HOXA13, thus validating this gene as a marker of HCCs. HOXA13, a determinant of gut primordia and posterior body structures, generates a fusion protein with NUP98 nucleoporin involved in leukaemogenesis. Transcriptome analysis on HCC/nontumourous liver mrnas, selected on the basis of HOXA13 overexpression, recognizes a set of deregulated genes. The matching of these genes with reported HCC transcriptome analysis identifies cell-cycle and nuclear pore related HCC phenotype displaying poor prognosis. HOXA13 and HOXA7 homeoproteins share a consensus sequence that physically links eif4e nuclear bodies acting on the export of specific mrnas (c-myc, FGF-2, VEGF, ODC, cyclin D1). A series of 47 frozen liver biopsies were collected from 35 patients identified by searching the files of the pathology institutes at the University of Basel, Switzerland, and at Federico II Medical School, Naples, Italy. Twelve patients underwent two liver biopsies, one of HCC and the second one of adjacent nontumourous liver tissue; 23 patients underwent a single HCC biopsy. Thirteen single liver biopsies were obtained during visceral surgery for gallbladder lithiasis and morbid obesity and were used as normal controls. A second series of 123 liver samples was used: 1) partially (57 HCC samples), to detect the transcriptome expression of the 33 out of 39 HOX genes included in the Affymetrix Chip 133A 2.0 and of the deregulated genes identified through the Affymetrix analysis of HOXA13 hyper-expressing HCC/nontumourous liver pairs; 2) in toto, to detect HOXA13 mrna real-time expression through G1-G6 HCC groups in the Zucman-Rossi laboratory. No substantial differences in the HOX gene expression were detectable by comparing normal and nontumourous livers, whereas major differences were found by comparing the frequency of active locus A HOX genes such as HOXA5, HOXA7, HOXA10 and HOXA13 in HCCs vs nontumourous and normal livers. Further, by analyzing the sequences of HOXA13 and HOXA7 homeoproteins, encoded by the two most deregulated locus A HOX genes of our HCC survey, we identified a consensus sequence (YQPWALP and YYVNALF=YXXXXLF) respectively responsible for their potential interaction with the rate-limiting step of eukaryotic cap-dependent translation initiation factor eif4e. In this study the comparison of HOX gene network expression in hepatocellular carcinomas and nontumourous liver tissue identified the HOX A locus as the part of the network more significantly involved in hepatocarcinogenesis. Among locus A HOX genes, HOXA13 appears to be a marker of hepatocellular carcinomas as well as an important transcriptional and post-transcriptional node in the cancerous liver s reversion to an embryonal stage towards gut primordia. The deregulation of genes identified through transcriptome analysis of highly HOXA13- expressing pairs of HCC/nontumourous liver matched to the G1-G6 classification of hepatocarcinomas identifies the poor prognosis HCC G3 group, suggesting the inclusion of HOX genes transcriptome as a potential prognostic tool in liver cancer. Prof. Dr. Luigi M. Terracciano Abteilung für Molekularpathologie Institut für Pathologie Universitätsspital Basel Schönbeinstrasse 40 CH-4003 Basel Phone +41 (0)61 265 28 49 Fax +41 (0)61 265 31 94 lterracciano@uhbs.ch

Thalmann George N. Impact of therapeutic and preventive strategies in prostate cancer on prostatespecific antigen (PSA), gene expression and tumor cell survival (OCS 01752-08-2005) Because of the progress made in the treatment of the primary tumour, mortality in patients with cancer is increasingly linked to progressive and metastatic disease, which is often occult at the time of diagnosis/therapy of the primary tumour. Despite treatment, tumours may progress by outgrowth of tumour cells resistant to treatment. It is unclear whether this selection is adaptive or clonal. Therefore, understanding the effect of preventive or therapeutic strategies on PSA and the tumour is essential. Aim of the study The working hypothesis of the project is that preventive and therapeutic agents may have an impact on the regulation and production of PSA and on gene expression in general. In addition, the cell subpopulation surviving treatment needs to be isolated and characterized. Methods and study design In order to study these interactions we used prostate cancer cell lines to test whether compounds used or under evaluation for prevention and treatment of prostate cancer have an impact on PSA production on the messenger RNA and protein level and on cancer cell growth. In addition, primary cell cultures from radical prostatectomy specimens were cultured under therapeutic conditions, and the therapy (hormone) refractory population was isolated and characterized, and tissue was used for the evaluation of potential novel prognostic markers. Study results We demonstrated that several compounds used for the prevention and therapy of prostate cancer, such as genistein or bicalutamide, inhibit PSA production, whereas genistein only inhibited hormone-sensitive cell growth. In primary cultures the treatment refractory hormone independent cell population evidenced a cancer stem-/progenitor-like phenotype that produces little of PSA but overexpresses genes of self-renewal and proliferation. Further, genes involved in angiogenesis (development of blood vessels) could be evaluated for their predictive value in patients undergoing radical prostatectomy. Recommendations and patient benefit Compounds foreseen for use in the prevention or treatment of prostate cancer should be evaluated for their influence on PSA expression prior to clinical use. The identification and characterization of the cell subpopulation surviving hormonal treatment of prostate cancer may allow development of novel treatment strategies for this disease. Finally, markers of neo angiogenesis could be tested for their predictive value in patients undergoing radical prostatectomy. A gene expression signature defining primary tumours with high malignant potential from such with low malignant potential could be determined. Prof. Dr. George Thalmann Klinik und Poliklinik für Urologie Inselspital Anna-Seiler-Haus CH-3010 Bern Phone +41 (0)31 632 36 64 urology.berne@insel.ch Theurillat Jean-Philippe Synthetic lethality in the context of autophagy-deficiency (KLS 02014-02-2007) Autophagy is a normal cellular process that mediates the breakdown of long-lived proteins. However, if autophagic activity is pathologically elevated, cells die as a consequence of self-digestion. Using an RNA-interference approach, we found that the loss of a specific signal-molecule termed S6K1 causes an excessive increase in autophagy flux followed by induction of programmed cell death (apoptosis). Constitutively, we found that S6K1 activity and hence survival of cancer cells is positively influenced by a novel oncogene called URI. Increased URI activity mediates resistance against many physiological and therapyinduced stressors. Study results We identified and described the function of the URI gene as an oncogene in ovarian cancer. URI translates into a protein that acts as a compound of a negative feedback loop dedicated to regulate S6K1 activity and ultimately influences the threshold for the induction of cell death (apoptosis). Normal cells die under physiological stress conditions, such as low availability of energy through induction of programmed cell death. However, when URI is upregulated, apoptosis induction is largely abolished. We found that about 35 % of patients with ovarian cancer display an upregulation of URI. One out of ten women exhibited, furthermore, an amplification of the URI gene. In the case of gene amplification, the gene is dramatically multiplied and integrated into the genome, which results in an increase in activity. Additionally, URI amplification could be detected in various other cancer types, suggesting that the importance of the present scientific results is not restricted to ovarian cancer. Interestingly, we were able to detect that women harbouring an amplified URI locus in their cancer genome were characterized by very aggressive tumour behaviour and failed to respond to chemotherapeutic treatment. In contrast to normal cells, URI is in those tumours essential for the survival of the tumour cells. On a molecular level, URI inhibits selectively in these tumour cells the inactivating function of a protein called PP1gamma on S6K1. As a direct consequence of our molecular understanding, we expect to find novel, more specific therapeutic approaches to treat patients with ovarian cancer characterized by URI amplification who do not respond to the standard chemotherapy regime. Patient benefit These findings will predict in the future the response of patients with ovarian cancer to a considered chemotherapy and help to judge whether a patient will benefit or not. Moreover, the results open up new perspectives for a more specific and personalized cancer treatment of women with ovarian cancer. This study, which is a result of collaboration with ETH Zurich, made a significant step towards the understanding of a novel oncogene, and will be published in 2011 in Cancer Cell. Dr. Jean-Philippe Theurillat Institut für klinische Pathologie UniversitätsSpital Zürich Schmelzbergstrasse 12 CH-8091 Zürich Phone +41 (0)44 633 76 58 jean-philippe.theurillat@usz.ch 147

148 Timmermann Beate Prospective evaluation of late effects and quality of life in childhood cancer after spot-scanning proton therapy at the Paul Scherrer Institute (OCS 01694-04-2005) Proton therapy offers promising characteristics to reduce the burden of radiation therapy. Especially children are highly vulnerable to radiation injury. Details on the clinical impact of physical characteristics of protons on the outcome are still unknown. Therefore, all children treated with proton beam therapy at the Paul Scherrer Institute (PSI) in Switzerland were to undergo prospective evaluation of quality of life (QoL) and treatment complications. Reliable, well-established tools for evaluation of treatment complications and quality of life were selected. The registry for late effects of irradiated children collects all data on radiation therapy in children. The forms were created by the working group for paediatric radiation oncology. It was agreed to collect all data on the children treated at PSI at the head office in Münster (Germany). Documentation consisted of data before therapy, 2 months after completion of therapy and yearly up-dates thereafter. For QoL, the Pediatric Quality Of Life (PEDQOL) instrument was chosen as the questionnaires for parents and children. The forms assessed different domains of QoL, including autonomy, body image, emotional behaviour, relation to friends and family and physical and cognitive performance. 120 children were registered into the RiSK registry study. Median age was 3.6 years (range, 1 18.3). The majority of children had bone or soft tissue sarcomas (n=56) or tumours of the CNS (n=40). Radiation doses ranged from 36 Gy to 75.8 Gy (med. 55.8). Predominantly mild acute reactions were observed, except for skin or bone marrow depression when simultaneous chemotherapy was applied (n=6). Higher scaled late complications were reported in lens (n=2) and brainstem (n=2). Brainstem complications were only observed after predisposing events. No correlation with treatment doses was found. As to the PEDQOL, in 142 children in total 626 forms were obtained, consisting of 142 basic information forms, 260 parental questionnaires, 135 children s questionnaires, and 89 parental forms for toddlers. In two-thirds of the children, significant morbidity was reported already before start of treatment. QoL seemed to be rated more positively by the children as compared to their parents and after 1 year even better as compared to their healthy references. Children older than 3 years of age showed improvement of QoL within 1 year after proton therapy. In children with tumours of the CNS, QoL seemed to be slightly more compromised as compared to children with sarcomas. First results after proton therapy are promising and suggest high tolerance and limited treatment burden despite relatively large doses of radiation therapy in a very young patient cohort. The compliance of the participants and their parents was high. To evaluate further details, larger cohorts and longer observation time is needed. Therefore, we suggest accompanying any innovative treatment method with studies on late effects and QoL. PD Dr. Beate Timmermann Westdeutsches Protonentherapiezentrum Essen Universitätsklinikum Essen Am Mühlenbach 1 D-45147 Essen Deutschland Phone +49 (0)201 723 18 01 Fax +49 (0)201 723 51 69 beate.timmermann@uk-essen.de von der Weid Nicolas Long-term outcome of childhood cancer: Incidence and spectrum of late effects (KLS 01605-10-2004) The Swiss Childhood Cancer Survivor Study (SCCSS) is a joint project of the Swiss Childhood Cancer Registry and the Swiss Paediatric Oncology Group and is run at the Institute for Social and Preventive Medicine of the University of Bern. All known survivors of paediatric cancer diagnosed in Switzerland received a postal questionnaire looking at current quality of life, health status, education, family situation and health behaviours. These data were compared to data of the general population and published in different scientific papers. The aim of the SCCSS was to know, in general and in many specific aspects, how survivors were doing, what kind of late effects they suffered from, to detect them as early as possible and to treat or alleviate them. Knowledge about long-term toxicities would aid the design of newer treatment strategies with the same efficacy and less morbidity. Included in the SCCSS were all children and adolescents diagnosed with a malignant disease in Switzerland between 1976 and 2003. We looked for current addresses in the former medical files of the patients and through an Internet-based search system. Survivors with established addresses received at their home a comprehensive health questionnaire in the years 2007 2010 with questions in following domains: current quality of life, somatic and psychological health, current medication, fertility/offspring, current use of the medical system (physician and hospital visits), health behaviours (drinking, smoking, use of illegal drugs), socio-economic status and education level. This prospective cohort study is very important for both patients and paediatric oncologists. It shows the spectrum of potential late effects and their dynamics and will be able to identify what risk factors are associated with what late toxicities. In the same way, we think that it will be possible also to demonstrate the beneficial effects of more recent therapies, which are much more adapted to the biological behaviour of the disease, sparing unnecessary toxicity in good risk patients ( tailored therapy, individualized oncology). In the last 50 years, paediatric cancer has moved from an almost always fatal to a usually curable disease. It is therefore compulsory to early detect, prevent, treat or at least reduce late toxicities in the majority of survivors. Another crucial topic is the transition from paediatric to adult medical care. This topic will be the

centre of a new study, based on the same data and also supported by the Foundation Cancer Research Switzerland (CRS) and the Swiss Cancer League (SCL). PD Dr Nicolas von der Weid Service de pédiatrie Centre hospitalier universitaire vaudois (CHUV) Rue du Bugnon 46 CH-1011 Lausanne Phone +41 (0)21 314 13 34 Fax +41 (0)21 314 33 32 nicolas.von-der-weid@chuv.ch Wodnar-Filipowicz Aleksandra Immunotherapy of human leukemia with natural killer cells: From bench to bedside (OCS 02175-02-2008) Acute leukaemias are rapidly progressing blood cell malignancies with poor prognosis. Front-line therapies with high doses of cytostatic agents and transplantation of allogeneic stem cells from the healthy bone marrow of donors offer the best chance of cure, but relapses are frequent and often fatal. This study aims at increasing the cure rate of patients with acute leukaemia by developing clinically-suitable approaches to immunotherapy with natural killer (NK) cells, a subpopulation of white blood cells capable of recognizing and eliminating malignant cells. The following goals have been achieved: 1) The protocol of large-scale clinical-grade in vitro expansion of highly purified human NK cell products, which was developed at the Laboratory of Experimental Haematology, was adapted to rigorous good manufacturing practice (GMP)-compliant conditions suitable for clinical implementation. NK cells were purified from the peripheral blood of 6 healthy blood donors, and cultured in closed air-permeable culture bags with certified culture medium and components approved for human use. NK cell numbers increased 117.0±20.0 fold in 19 days. 2) GMP-certified cell sorting was introduced to obtain cells with a high anti-leukaemic potential, called single KIR NK cells. The subsequent GMP-compliant expansion of cells was 268.3±66.8 fold, with a contaminating T cell content of only 0.006 %±0.002 %. The cell sorting step preceding the expansion step offered important advantages of increased tumour specificity with reduced culture volume, as well as lowered the costs of NK cell expansion. 3) To implement our project in clinical practice, the GMP Laboratory was designed and built in 2010 at the Division of Diagnostic Hematology of University Hospital Basel. The construction and infrastructure conform to current regulations in Switzerland. The personnel, including academics and technicians, were trained, and the standard operating procedures were established. After the final certification of the GMP laboratory by Swissmedic, the feasibility, safety and efficacy of administration of expanded NK cells will be evaluated in phase I/II trials in the following clinical settings: a) in patients with leukaemia, after haploidentical stem cell transplantation; b) in patients with multiple myeloma, after autologous transplantation; and c) in elderly leukaemia patients not eligible for intensive chemotherapy and stem cell transplant. 4) Our experimental studies designed to characterize the efficacy of alloreactive NK cells against leukaemia demonstrated that NK cells generated ex vivo with a GMP-compatible expansion protocol specifically recognize and destroy primary leukaemic blasts. We provided the first evidence that expanded single-kir NK cells had a significant tumour-reducing effect in vivo in mice inoculated with human leukaemic cells. We also showed that NK cells are active against leukaemic stem cells, a small cell population responsible for both the initiation and recurrence of the malignancy, and therefore representing an important target for immunotherapy. The preclinical studies described in this project delivered important information as to the anti-leukaemic potential of high dose of activated NK cells, and the obtained results are contributing to the development of novel immunotherapeutic approaches increasing the chances of leukaemia cure. Our translational project combines the expertise of the Laboratory of Experimental Hematology in the Department of Biomedicine and the Stem Cell Transplant Team at the Hematology Clinic in the University Hospital Basel. Prof. Dr. Aleksandra Wodnar-Filipowicz Basel Stem Cell Center of Competence Medizinische Fakultät Universität Basel Klingelbergstrasse 61 CH-4056 Basel Phone +41 (0)61 265 33 87 aleksandra.wodnar-filipowicz@unibas.ch Wodnar-Filipowicz Aleksandra Role of the natural killer cell receptors NCR and KIR in immune defence against human leukemia (OCS 01664-02-2005) Acute leukaemias are rapidly progressing blood cell malignancies with poor prognosis. Therapies with high dose of cytostatic agents and transplantation of stem cells offer the best chance of cure, but relapses are frequent and often fatal. Immunotherapy with natural killer (NK) cells represents a novel strategy to eliminate the residual malignant clones and prevent recurrence of the disease. This research project addressed the mechanisms of antileukaemic function of human NK cells. In a collaborative effort with the clinics of haematology in Basel and Aarau and in Warsaw, Poland, we were able to acquire a large number of leukaemia patient-derived blood and bone marrow samples. We demonstrated that expression of cell surface molecules serving as ligands for activating and inhibitory NK cell receptors defines the recognition and elimination of tumour cells by the cytotoxic function of NK cells. Therefore, our next goal was to design experimental approaches to enhance the leukaemia recognition process by means of selecting the anti-leukaemic, alloreactive NK cell populations. To strengthen the activating interactions between NK cells and leukaemic targets, we developed pharmacological treatments that enhanced the expression of cell surface ligand molecules specific for NK cells. To optimize the NK cell-mediated immunity against 149

150 recurrence of the disease, we addressed the recognition of leukaemic stem cells by NK cells. This is a small subpopulation of malignant cells that is implicated in the development and persistence of leukaemia. Results of these studies demonstrated that NK cell therapy, together with the use of pharmacological antineoplastic drugs, should be considered as an innovative combinatorial approach for treatment of leukaemia. The important outcome of our project is the translational bench to bedside clinical trial initiated in 2008 at University Hospital Basel. Altogether, the results of our studies contributed to a better understanding of the specific NK cell-leukaemia interactions and to the development of novel approaches towards curing human leukaemia. Prof. Dr. Aleksandra Wodnar-Filipowicz Basel Stem Cell Center of Competence Medizinische Fakultät Universität Basel Klingelbergstrasse 61 CH-4056 Basel Phone +41 (0)61 265 33 87 aleksandra.wodnar-filipowicz@unibas.ch Zaman Khalil Monitoring of angiogenesis-related molecules during first line chemotherapy with bevacizumab and pegylated liposomal doxorubicin for advanced stage breast cancer: A substudy of the SAKK 24/06 trial (OCS 02029-02-2007) The anti-angiogenic drug Avastin is currently used in the treatment of different malignancies including breast cancer. Until now, no identified factor had been identified predicting benefit from Avastin. Many angiogenesis associated molecules are detectable in the blood of patients with cancer. We monitored prospectively six angiogenesis related factors in patients with advanced stage breast cancer treated with a combination of Avastin and pegylated liposomal doxorubicin (PLD) in a phase II trial of the Swiss Group for Clinical Cancer Research (SAKK). Methods Patients received Caelyx and Avastin every 2 weeks for a maximum of 12 administrations, followed by Avastin monotherapy until progression or severe toxicity. Blood samples were collected at baseline, after 2 months of therapy, then every 3 months and at treatment discontinuation. Enzyme-linked immunosorbent assays were used to measure vascular endothelial growth factor (VEGF), placental growth factor (PlGF), matrix metalloproteinase-9 (MMP-9) and soluble VEGF receptors, svegfr-1, svegfr-2 and svegfr-3. The natural log transformed (ln) data for each factor was analyzed by analysis of variance (ANOVA) model to investigate differences between the mean values of the subgroups of interest (where a=0.05), based on the best tumour response. Results 132 samples were collected in 41 patients. The mean of baseline MMP-9 levels was significantly higher in patients with tumour response (p=0.0202, log fold change= 0.8786) or disease control (p=0.0035, log fold change= 0.8427) compared to those with disease progression. Higher MMP-9 level was also a predictor of better progression-free survival (p=0.0417, hazard ratio=0.574, 95 % CI=0.336 0.979), even when other prognostic factors were considered in a multivariate cox proportional hazards model (p=0.0266). MMP-9 level allows to distinguish two groups in the treated population, one with higher levels and longer progression-free survival and the other with lower levels and rapidly progressing cancer during treatment (p=0.0408). The mean level of baseline svegfr-1 was significantly lower in patients with disease control than those with progression (p-value=0.0008, log fold change= 1.0289). No strong correlation was shown for the other factors measured. Conclusions Higher baseline levels of MMP-9 could predict better efficacy of the combination of Avastin and Caelyx and a longer progression free survival. Clinical implications for the patients Only a limited number of patients with breast cancer benefit from the association of Avastin with their chemotherapy. If our exploratory results are confirmed in the future, MMP-9 could allow a better selection of the patients who will benefit from Avastin and consequently improve the benefit/risk ratio of this controversial treatment. Dr Khalil Zaman Centre pluridisciplinaire d oncologie (CePO) Centre hospitalier universitaire vaudois (CHUV) Rue du Bugnon 46 CH-1011 Lausanne Phone +41 (0)79 556 78 01 Secrétariat +41 (0)21 314 01 68 Fax +41 (0)21 314 02 00 khalil.zaman@chuv.ch Zhong Xiao Yan Investigating tumour-derived methylation DNA in circulation as markers for noninvasive screening, early diagnosis, monitoring and determination of the prognosis of breast cancer (OCS 01993-02-2007) The discovery of cell-free DNA in plasma and serum samples offers new diagnostic possibilities in two crucial areas prenatal genetic diagnosis and cancer detection. In the prenatal area, we have recently shown that both cell-free foetal DNA and foetal cells in maternal blood could be used for non-invasive prenatal diagnosis regarding genetic diseases and pathological pregnancies. We were able to detect cell-free foetal DNA earlier, more frequently and in greater amounts than foetal cells in the maternal circulation. In the cancer area, we have found that a high level of cell-free DNA in plasma was elevated in breast cancer and was related to tumour size and distant metastases, suggesting a potential for clinical applications. In order to develop a non-invasive blood test, we intend to identify breast cancer-related DNA methylation changes in tumour tissues as tumour biomarkers. DNA methylation analysis is a rapidly developing field. However, studies demonstrating its usefulness are still limited due to the fact that no one technique is superior. A new quantitative high-throughput MassCLEAVE TM assay (Sequenom) based on MALDI-TOF MS system enables dis-

covering of methylation, discriminating between methylated and non-methylated DNA and quantifying the methylation levels of DNA. We were able to use the MALDI-TOF MS-based assay to analyze DNA methylation status of 22 genes (APC, BIN1, BMP6, BRCA1, BRCA2, CADHERIN 1, CST6, DAPK1, EGFR, ESR2, GSTP1, NES1, Nm23-H1, P16, P21, PR, Prostasin, RAR-b, RASSF1, SRBC, TIMP3, TP53) in breast cancer (BC). They are mostly tumour suppressor genes (TSGs) involved in cancerogenesis, metastasis, drug resistance and response to hormone therapy in BC. We analyzed the methylation status of a total of 42,528 CpG dinucleotides on 22 genes in 96 different paraffin-embedded tissues (48 breast cancerous tissues and 48 paired normal tissues). A two-way hierarchical cluster analysis was used to classify methylation profiles. In this study, 10 hypermethylated genes (APC, BIN1, BMP6, BRCA1, CST6, ESRb, GSTP1, P16, P21 and TIMP3) were identified to distinguish between cancerous and normal tissues according to the extent of methylation. Individual assessment of the methylation status for each CpG dinucleotide indicated that cytosine hypermethylation in the cancerous tissue samples was mostly located near the consensus sequences of the transcription factor binding sites. These hypermethylated genes may serve as biomarkers for developing a non-invasive blood test for management of patients with breast cancer. Prof. Dr. Xiao Yan Zhong Forschungsgruppe pränatale Medizin und gynäkologische Onkologie Departement Biomedizin Universität Basel Hebelstrasse 20 CH-4031 Basel Phone +41 (0)61 328 69 86 Fax +41 (0)61 265 93 99 xzhong@uhbs.ch

152 Zucca Emanuele A prospective clinico-pathologic study of primary mediastinal B-cell lymphoma (PMBCL) (OCS 01709-04-2005) The need for radiotherapy in patients with primary mediastinal B-cell lymphoma (PMBCL) treated with the modern immunochemotherapy regimens is an unresolved issue that is becoming more and more controversial. The IELSG-26 study (International Extranodal Lymphoma Study Group) aims to obtain data on treatment outcomes following anthracycline-containing immunochemotherapy regimens, with or without mediastinal radiotherapy, the latter depending upon the practice of the participating institutions. Main endpoint of the study is to determine the response rate evaluated by positron emission tomography scans (18FDG PET-CT) following chemo-immunotherapy. The study enrolled 125 patients with PMBCL treated using either the R-CHOP or the R-MACOP-B chemotherapeutic regimen; 123 received consolidation radiotherapy. The recruitment ended in November 2010. Treatment results were monitored using 18-F-FDG PET-CT scan performed baseline, at 3 4 weeks after the end of chemotherapy and 2 months post-radio-therapy, respectively. The PET CR was defined according to the criteria of the International Harmonization Project (Cheson et al., Journal of Clinical Oncology 2007). The central PET images qualitative review by an expert nuclear medicine specialist is ongoing and has included 61 patients up to now. The PET-CT scan became negative at the end of chemotherapy in only 49 % of patients. The agreement between central review and on site reporting was 70 % (43/61) with increase on central review of the positive cases (from 39 % to 51 %) due mainly to the on site underestimation of the minimal residual 18FDG activity at the end of treatment. The rate of patients with persistent PET-positive scans at the end of immunotherapy in this study seems higher than in the non-mediastinal large cell lymphoma. This might partly depend on the relatively short interval between end of chemotherapy and imaging (which may affect the rate of false positive scans). Analysis of the PET response and its correlation with clinical outcome in the entire study population is awaited. It will be of paramount importance for the design of future clinical trials aimed at defining the increasingly debated role of radiotherapy. PD Dr. Emanuele Zucca International Extranodal Lymphoma Study Group (IELSG) Istituto oncologico della Svizzera italiana (IOSI) Ospedale San Giovanni CH-6500 Bellinzona Phone +41 (0)91 811 90 40 Fax +41 (0)91 811 91 82 emanuelezucca@yahoo.com Further completed research projects from July 2008 to December 2010 Cozzi Luca OCS 01821-02-2006 CHF 80,800. Servizio di fisica medica, Istituto oncologico della Svizzera italiana (IOSI), Ospedale regionale di Bellinzona e valli, Bellinzona Heterogeneity management in advanced algorithms for photon dose calculation and the clinical impact on breast and lung cancer radiotherapy. Validation of existing models against experimental studies, Monte Carlo simulations and determination of potential Garayoa Elisa Garcia KLS 02040-02-2007 CHF 150,700. Zentrum für radiopharmazeutische Wissenschaften, Paul Scherrer Institut (PSI), Villigen Development of new bombesin-based radiopharmaceuticals with improved pharmacokinetics as potential imaging and therapeutic agents for bombesin receptor-positive tumours Hoek Keith OCS 01927-08-2006 CHF 145,500. Dermatologische Klinik, Medizinbereich Trauma-Derma-Rheuma-Plastische Chirurgie, UniversitätsSpital Zürich, Zürich Clinical implications of Wnt signal-driven regulation of melanoma metastatic potential Stahel Rolf A. OCS 01915-08-2006 CHF 148,800. Klinik und Poliklinik für Onkologie, Medizinbereich Innere Medizin-Onkologie, UniversitätsSpital Zürich, Zürich SAKK trial 17/04 on neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma (MPM) with or without hemithoracic radiotherapy, including translational research

Clinical research List of approved research projects in 2009/2010 Total funds allocated CHF 7,097,850. Aebi Stefan KFS 02689-08-2010 CHF 260,300. Medizinische Onkologie, Luzerner Kantonsspital, Luzern IBCSG 39-10 / MA.32: A phase III randomized trial of the effect of metformin versus placebo on recurrence and survival in early stage breast cancer Anderle Pedone Pascale OCS 02303-08-2008 CHF 195,000. Institut für Biochemie und molekulare Medizin, Universität Bern, Bern Exploiting transporters in the tumor-stroma interface to aim for a more efficient chemotherapy 153 Bertoni Francesco KLS 02403-02-2009 CHF 150,000. Gruppo genomica funzionale e linfomi, Laboratorio di oncologia sperimentale, Istituto oncologico della Svizzera italiana (IOSI), Bellinzona Anaplastic large cell lymphoma: One or more entities? Bourquin Jean-Pierre KFS 02453-08-2009 CHF 125,500. Abteilung Onkologie, Kinderspital Zürich, Universitäts-Kinderkliniken, Zürich Pre-clinical evaluation of a new pharmacological approach using obatoclax for chemosensitization of drug resistant childhood acute lymphoblastic leukemia Bourquin Jean-Pierre KFS 02583-02-2010 CHF 238,000. Abteilung Onkologie, Kinderspital Zürich, Universitäts-Kinderkliniken, Zürich Comprehensive analysis of the cell surface proteome of childhood refractory ALL for identification of new diagnostic and therapeutic targets Carbone Giuseppina KFS 02573-02-2010 CHF 305,100. Laboratorio di oncologia sperimentale, Istituto oncologico della Svizzera italiana (IOSI), Bellinzona Deregulated ETS transcriptional network and clinical implications for prostate cancer progression Cathomas Gieri KLS 02392-02-2009 CHF 248,550. Kantonales Institut für Pathologie, Kantonsspital Liestal, Liestal The role of polyomavirus in the development of Merkel cell and epithelial skin carcinomas Cavalli Franco KLS 02399-02-2009 CHF 157,550. Istituto oncologico della Svizzera italiana (IOSI), Ospedale San Giovanni, Bellinzona A randomised phase II trial on primary chemotherapy with high-dose methotrexate (HD-MTX) and high-dose cytarabine (HD-AraC) with or without thiotepa and with or without rituximab, followed by brain irradiation vs. high-dose chemotherapy supported by autologous stem cell transplantation (ASCT) for immunocompetent patients with newly diagnosed primary central nervous system lymphoma (PCNSL) Foti Michelangelo KFS 02502-08-2009 CHF 307,400. Département de physiologie cellulaire et métabolisme, Faculté de médecine, Centre médical universitaire (CMU), Université de Genève, Genève Role of dietary free fatty acids, microrna-21 and PTEN in liver cancer Gruber Günther KFS 02527-02-2010 CHF 150,700. Institut für Radiotherapie Zürich, Klinik Hirslanden, Zürich BIG 3-07: A randomised phase-iii study of radiation doses and fractionation schedules for ductal carcinoma in situ (DCIS) of the breast Hegi Monika E. KFS 02670-08-2010 CHF 198,300. Laboratoire de biologie et génétique des tumeurs, Service de neurochirurgie, Centre hospitalier universitaire vaudois (CHUV), Lausanne Targeting the EGFR/PI3K pathway in glioblastoma, what matters? Heim Markus Hermann KLS 02522-02-2010 CHF 218,300. Klinik für Gastroenterologie und Hepatologie, Universitätsspital Basel, Basel Hepatocarcinogenesis in chronic hepatitis C

Heinimann Karl KFS 02489-08-2009 CHF 133,000. Forschungsgruppe Humangenetik, Abteilung für medizinische Genetik UKBB, Departement Biomedizin, Universität Basel, Basel mirna expression profiling in Lynch syndrome-associated colorectal cancer Körner Meike OCS 02349-02-2009 CHF 108,500. Abteilung für Zellbiologie und experimentelle Krebsforschung, Institut für Pathologie, Universität Bern, Bern In vitro evaluation of the glucagon-like peptide 2 receptor expression in human cancer: molecular basis for in vivo tumor radiotargeting Kristiansen Glen KFS 02465-08-2009 CHF 171,200. Institut für klinische Pathologie, UniversitätsSpital Zürich, Zürich Identification of a clinically applicable prognostic RNA signature of prostate cancer 154 Mermod Nicolas KFS 02446-08-2009 CHF 360,100. Laboratoire de biotechnologie moléculaire, Institut de biotechnologie, Université de Lausanne, Lausanne Evaluation of AP2 protein-binding microarrays for breast tumor profiling and for the prognosis of the response to chemotherapies Moeckli Raphaël KFS 02637-08-2010 CHF 107,200. Institut de radiophysique, Département de radiologie, Centre hospitalier universitaire vaudois (CHUV), Lausanne Evaluation of second cancer risk models in radiotherapy for average and high dose levels Müller Beatrice U. KFS 02449-08-2009 CHF 297,900. Departement für allgemeine Innere Medizin und klinische Forschung, Inselspital, Bern Transcriptional dysregulation during myeloid transformation in acute myeloid leukemia (AML) Nadal David KLS 02375-02-2009 CHF 227,900. Abteilung Infektiologie und Spitalhygiene, Medizinische Klinik, Kinderspital Zürich, Universitäts-Kinderkliniken, Zürich Is endemic Burkitt s lymphoma really promoted by chronic innate immunity triggering by malaria infection? Niggli Felix KLS 02578-02-2010 CHF 298,300. Onkologielabor, Kinderspital Zürich, Universitäts-Kinderkliniken, Zürich Constitution of a national study centre for the European acute lymphoblastic leukaemia trial (AIEOP-BFM ALL 2009) on behalf of the Swiss paediatric oncology group (BFM-CH) Ozsahin Hulya KLS 02656-08-2010 CHF 155,300. Unité d onco-hématologie pédiatrique, Hôpitaux universitaires de Genève (HUG), Genève SIOPEL International Childhood Liver Tumour Strategy Group a comprehensive research program and a randomized trial for standard risk hepatoblastoma Pabst Thomas KLS 02520-02-2010 CHF 349,100. Institut für medizinische Onkologie, Inselspital, Bern Transcriptional dysregulation of the myeloid key transcription factor CEBPA in human acute myeloid leukemia Petignat Patrick KFS 02691-08-2010 CHF 230,600. Unité d oncogynécologie chirurgicale, Hôpitaux universitaires de Genève (HUG), Genève Self-sampling for HPV in women who do not undergo routine cervical cancer screening: A randomized trial Renevey Philippe KFS 02681-08-2010 CHF 138,400. Centre suisse d électronique et de microtechnique (CSEM), Neuchâtel Automatic vocal aid system for laryngectomees with improved voice quality Resink Theresa KFS 02447-08-2009 CHF 343,000. Forschungsgruppe Signaltransduktion, Departement Biomedizin, Universität Basel, Basel T-cadherin: a functional determinant and early prognostic marker for malignant transformation of squamous cell carcinomas Roth Arnaud KFS 02697-08-2010 CHF 202,700. Unité d oncochirurgie, Hôpitaux universitaires de Genève (HUG), Genève Molecular heterogeneity and prognostic markers in colon cancer by analysis of gene expression and gene mutation data

Rothermundt Christian KFS 02641-08-2010 CHF 76,500. Fachbereich Onkologie/Hämatologie, Kantonsspital St. Gallen, St. Gallen Metformin in castration resistant prostate cancer. A multicenter phase II trial of the SAKK (Swiss Group for Clinical Cancer Research) (SAKK08/09) Rufer Nathalie KFS 02635-08-2010 CHF 210,300. Centre Ludwig de recherche sur le cancer, Université de Lausanne, Lausanne Structural and functional studies of T-cell receptors specific for tumor antigens: Implications for immunotherapy in cancer patients Schwaller Jürg OCS 02357-02-2009 CHF 232,000. Forschungsgruppe Kinder-Leukämie, Departement Biomedizin, Universitätsspital Basel, Basel Exploring new molecular therapeutic targets in MLL-X acute leukemia Skoda Radek KLS 02398-02-2009 CHF 324,100. Forschungsgruppe experimentelle Hämatologie, Departement Biomedizin, Universität Basel, Basel The pathogenesis of myeloproliferative disorders 155 Stenner-Liewen Frank KFS 02423-04-2009 CHF 216,700. Medizinische Onkologie, UniversitätsSpital Zürich, Zürich Establishment of GOLPH2 as a serum marker in hepatocellular carcinoma (within the SAKK 77/08 trial) and in bile duct cancer for routine clinical use Zeller Rolf OCS 02368-02-2009 CHF 360,350. Forschungsgruppe Entwicklungsgenetik, Departement Biomedizin, Universität Basel, Basel Functional analysis of modulators of SHH pathway activity during the formation of medulloblastomas: a mechanistic study with clinical relevance Approved bursaries in 2009/2010 Total funds allocated: CHF 621,250. Arber Barth Caroline BIL KFS 02506-08-2009 CHF 109,300. Targeting B acute lymphoblastic leukemia by adoptive transfer of leukemia-specific T-cells after cord blood transplantation Zielort: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, USA Baumann Michael BIL KLS 02589-02-2010 CHF 28,750. Treatment of naive and fludarabine-refractory CLL in the TCL-1 mouse model with IPI-926 and other hedgehog pathway inhibitors Zielort: Labor für molekulare Biologie und Immunologie der CLL, Klinik I für Innere Medizin, Universität Köln, Köln, Deutschland Bohanes Pierre BIL KLS 02591-02-2010 CHF 53,500. Intratumoral gene expression and germline polymorphism of patients with gastric cancer treated with chemoradiation in the Southwest Oncology Group protocol (SWOG) 9008 Zielort: USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA Dedes Konstantin BIL KLS 02406-02-2009 CHF 60,000. Identification of therapeutic targets for invasive ductal carcinomas of no special type Zielort: Breakthrough Breast Cancer Research Center, Institute of Cancer Research and the Royal Marsden Hospital, London, United Kingdom Omlin Aurelius BIL KFS 02592-02-2010 CHF 136,000. A prospective comparison of three different methods of circulating tumor cell (CTC) isolation and characterization utilizing multi-colour immunofluorescence (IF) and fluorescent in-situ hybridization (FISH) in advanced cancer patients Zielort: Drug Development Unit, Royal Marsden Hospital, Sutton Surrey, United Kingdom

Riggi Nicolò BIL KFS 02717-08-2010 CHF 88,400. The role of micrornas in Ewing s sarcoma cancer stem cells Zielort: Institut universitaire de pathologie de Lausanne (IUP), Centre hospitalier universitaire vaudois (CHUV), Lausanne Sùva Mario BIL KFS 02590-02-2010 CHF 104,300. Role of the polycomb group protein EZH2 in glioblastoma cancer stem cells Zielort: Harvard Medical School, Massachusetts General Hospital, Boston, USA Wirth Johann Gregory BIL KLS 02593-02-2010 CHF 41,000. Apoptosis resistance in prostate cancer, with a focus on the use of patient tissue samples Zielort: Harvard Medical School, Massachusetts General Hospital, Boston, USA 156 Clinical research Presentation of approved research projects in 2009/2010 Aebi Stefan IBCSG39-10/MA.32: A phase III randomized trial of the effect of metformin versus placebo on recurrence and survival in early stage breast cancer (KFS 02689-08-2010) Duration: 01.09.2010 01.09.2013 A large clinical trial is investigating whether metformin, a drug used for the treatment of diabetes, diminishes the risk of recurrence in patients with early breast cancer. The trial was organized by the National Cancer Institute of Canada (NCIC) Clinical Trials Group. Swiss patients can participate through the International Breast Cancer Study Group. All patients will receive prophylactic (adjuvant) therapy according to current standards; this study aims to compare the frequency of relapses of patients on additional metformin with patients on standard therapy. Patients who consent will be randomly allocated to the control group or to the metformin group. In addition to the number of relapses, biological properties of the tumours will be studied (e. g. presence of insulin receptors) to find out which patients are most likely to respond to therapy. This trial will include 3,500 patients worldwide. It is being conducted by academic researchers without any funding from the pharmaceutical industry. This clinical trial will demonstrate whether a simple therapy with a well-known drug improves the prognosis of women with breast cancer. Prof. Dr. Stefan Aebi Medizinische Onkologie Luzerner Kantonsspital CH-6000 Luzern 16 Phone +41 (0)41 205 58 60 Fax +41 (0)41 205 58 62 Anderle Pedone Pascale Exploiting transporters in the tumor-stroma interface to aim for a more efficient chemotherapy (OCS 02303-08-2008) Duration: 01.06.2009 01.06.2012 Tumour cells within the same carcinoma are heterogeneous and contribute to different aspects of tumour progression. Whereas some are mainly responsible for tumour growth and are in a proliferating state, others at the invasive front are responsible for invasion into the surrounding tissue. It has become clear in recent years that the behaviour of a tumour does not solely depend on the tumour cells alone but also on the interaction of the tumour cells with the surrounding tissue. However, still little is known on how tumour cells respond to their microenvironment. A better understanding of the underlying processes could eventually lead to improved therapy. In this project we are studying the expression and functions of membrane transporters that are known or very likely to be involved in tumour progression and may also serve as drug carriers. Using laser-dissection microscopy of tumour and healthy colon tissue from freshly operated patients, we will extract RNA to perform genome-wide profiling. Microarray expression data will be further validated with RT-PCR and protein expression patterns with immunofluorescence in human colon sections. Appropriate cell lines will be selected based on the gene expression profile and used for drug sensitivity and resistance testing. Eventually, we will test the effect of selected chemotherapeutics in vivo in mouse tumour models. In general, studying the tumour-stroma interaction is still an emerging field. In particular, the expression of transporters has hardly been studied in the context of tumourstroma interaction or in the context of the heterogeneity of a solid tumour. Thus, a better understanding of the role

of transporters with respect to chemosensitivity and chemoresistance in the various tumour cell subpopulations will contribute to a more efficient chemotherapy. Dr. Pascale Anderle Pedone Institut für Biochemie und molekulare Medizin Universität Bern Bühlstrasse 28 Postfach CH-3000 Bern 9 Phone +41 (0)31 631 47 39 Fax +41 (0)31 631 37 37 pascale.anderle@mci.unibe.ch Bertoni Francesco Anaplastic large cell lymphoma: One or more entities? (KLS 02403-02-2009) Duration: 01.08.2009 01.08.2011 The recent 2008 World Health Organization (WHO) classification divides anaplastic large cell lymphoma (ALCL) into two distinct subgroups based mainly on the presence or absence of translocations affecting the anaplastic lymphoma kinase (ALK) gene. It is well accepted that patients with ALK positive ALCL are a distinct group sharing unique phenotypic and well-defined genetic and clinical features. Although the general clinical presentations and peculiar translocations and/or genetic events differ in the ALK positive and ALK negative ALCL subgroups, the question as to how related the two types of ALCL are and whether ALK negative ALCL may represent a subset of peripheral T-cell lymphomas, not otherwise specified (PTCL, NOS) remains open. The aim of this project is to focus on the genetic events underlying the pathogenesis of ALCL. The dual aim is to provide better tools to differentiate the individual lymphoma types and to identify genes that might represent new therapeutic targets. Material and methods The study is being performed on a large series of ALK positive and ALK negative ALCL clinical samples; this has been made possible thanks to an international network of collaborating investigators. For genomic profiles we are using Affymetrix Human Mapping SNP6 Arrays and for gene expression profiling Affymetrix U133 plus 2.0. We are also data mining a very large dataset of proprietary and public T-cell NHL gene expression profiles. Results Ongoing are: data mining, validation of regions of interests and characterization of a gene identified by data mining of the gene expression profiles. The project is proceeding according to plan. Dr. Francesco Bertoni Laboratorio di oncologia sperimentale Istituto oncologico della Svizzera italiana (IOSI) Via Vincenzo Vela 6 CH-6500 Bellinzona Phone +41 (0)91 820 03 67 Fax +41 (0)91 820 03 97 frbertoni@mac.com Bourquin Jean-Pierre Pre-clinical evaluation of a new pharmacological approach using obatoclax for chemosensitization of drug resistant childhood acute lymphoblastic leukemia (KFS 02453-08-2009) Duration: 01.03.2010 01.03.2011 Using a preclinical model that is based on representative cases with highly resistant disease, we have established a new rationale for chemosensitization in acute lymphoblastic leukaemia (ALL). A small molecule that is thought to act as an antagonist of critical regulators of programmed cell death, obatoclax mesylate, very effectively restored the response to conventional chemotherapeutic agents in ALL cells that were otherwise completely refractory to these conventional chemotherapeutic agents. Unexpectedly, combination of obatoclax with dexamethasone, one of the most important drugs for ALL treatment, triggered a new type of programmed cell death specifically in resistant leukaemia cells but not in chemosensitive ALL cells, providing a strong rationale for a selective therapeutic targeting of resistant leukaemia cells. Interestingly, combination of obatoclax with other cytotoxic agents triggered a classical cell death pathway, the mitochondrial apoptotic pathway, suggesting that this agent interferes with critical mechanisms at the interface of two cell death pathways. Based on our work, which is in part published in the Journal of Clinical Investigation, a proposal for a clinical phase I trial was developed under the auspices of the leading group of experts in Europe, regrouped in the resistant disease committee of the international BFM Study Group (BFM stands for Berlin-Frankfurt-Münster to credit the important contribution of the first founders who paved the way to successful chemotherapy regimen for ALL). The aim of this study is to evaluate toxicity and gain first evidence for activity of the combination of obatoclax and dexamethasone in patients with relapsed or refractory ALL. This approach would then be taken forward as an investigational phase II window for high risk patients in first relapse to evaluate clinical activity. This trial will also contribute to designing an experimental therapy with several chemotherapeutic agents for patients with refractory disease. This proposal has received a lot of attention in the field and was declared as one of the priorities for drug development for refractory ALL by IBFM. To further improve and accelerate the clinical development of obatoclax as chemosensitizer, we established a larger number of cases with relapsed and refractory B-cell precursor (BCP) and T-cell ALL using our leukaemia xenograft model. The aim was to understand whether resistance to chemosensitization with obatoclax could occur in this patient population and to identify biomakers that would help predict a response to the drug. Interestingly, we could not find any case that would not respond to the combination of obatoclax with chemotherapeutic agents in BCP-ALL but detected several resistant cases in T-ALL. Sensitization activity to the glucocorticoid drug dexamethasone using obatoclax was clearly associated with inhibition of mtor kinase activity, an important signalling node that integrates signals from different pathways to promote tumour growth. We used our leukaemia xenograft model to test the possibility to follow mtor kinase 157

158 activity at the single cell level in the peripheral blood of treated animals, using flow cytometry. We consistently detected reduction of mtor kinase activity in leukaemias that respond to treatment but not in leukaemias that were resistant to this approach. We will therefore include this method in the planned clinical trial to obtain evidence for biological activity of this approach in patients under treatment with obatoclax and dexamethasone. Furthermore, the identification of independent ALL cases that were resistant to obatoclax-mediated chemosensitization provides a strong basis to better understand the molecular mechanisms that are involved for drug activity. Finally, having first shown that we could prevent disease progression with a combination of obatoclax and dexamethasone in an in vivo mouse xenograft model, we now showed that we can induce remissions in mice with very high disease burden with a treatment that corresponds to the type of exposition patients will receive as treatment. Taken together, we have been able to establish a new rationale to achieve chemosensitization using a preclinical model that is representative of the patient population at need. We will continue to work on improving our understanding of the complex underlying mechanisms that are involved to achieve this type of treatment response, in order to provide a better methodology to predict which patients will benefit from this treatment approach. Our study illustrates how such a platform will be used to accelerate and improve the preclinical evaluation of new therapeutic options. We hope that this type of approach will contribute to improving the dismal outcome of patients with refractory disease and serve to reduce treatment in general. PD Dr. Jean-Pierre Bourquin Abteilung Onkologie Kinderspital Zürich Universitäts-Kinderkliniken Steinwiesstrasse 75 CH-8032 Zürich Phone +41 (0)44 266 73 04 jean-pierre.bourquin@kispi.uzh.ch Bourquin Jean-Pierre Comprehensive analysis of the cell surface proteome of childhood refractory ALL for identification of new diagnostic and therapeutic targets (KFS 02583-02-2010) Duration: 01.08.2010 01.08.2012 Acute lymphoblastic leukaemia (ALL) of childhood is a deadly disease for which salvage of therapy-resistant cases remains challenging. Leukaemia-associated cell surface markers have been very useful for leukaemia classification and may provide better possibilities for selective therapeutic intervention. Here we exploit the power of combining two experimental platforms to generate an unprecedented view at the cell surface landscape in childhood ALL. We have established a reliable methodology to expand small amounts of leukaemia cells directly from patient samples, while keeping the dominant genetic and phenotypic features of the original leukaemia. We are now in a unique position to perform biomedical studies that were previously deemed impossible due to limiting material. In collaboration with the Institute of Molecular Systems Biology at the ETH Zurich, we have mapped hundreds of cell surface proteins on leukaemia cells from patients with highly resistant or very chemosensitive disease. We took advantage of a proteomic technology that relies on the specific tagging of cell surface proteins on specific sugar structures on the protein backbone directly on the surface of intact living cells. Small peptide fragments can then be purified based on the presence of such a tag and analyzed simultaneously using mass spectrometry, a technique that enables us to determine the protein composition in a large mixture that is obtained from cellular preparations after the identification of these protein fragments. The proteomics-based approach completely recapitulated the typical pattern of leukaemia-associated markers for ALL classification, as it is usually analyzed by multicolour flow cytometry at diagnosis in the clinical setting. Importantly, we can detect proteins that are universally expressed in ALL or in contrast overrepresented in resistant cases. Different clinically relevant research questions are being pursued based on this dataset. Firstly, we identified a cell surface marker that is characteristic for a previously unrecognized subtype of ALL. Because expression at the protein level corresponds to gene expression levels for this marker, we have been able to expand this analysis to different, very large collections of patient samples that were available from two European clinical studies. We thereby identified a rare leukaemia subgroup, which could be consistently found at the same frequency in independent large cohorts of patients and only in groups with a higher risk of relapse. This new subtype carries a characteristic gene expression signature that is characteristic for an inflammatory response. We are now evaluating the effect of a large number of therapeutic agents to target the corresponding pathways. Second, we are exploring the importance of candidate cell surface proteins for the interaction of leukaemia cells with their microenvironment in the bone marrow, providing new targets to dislodge ALL cells from their protective niche. Taken together, the combination of the mouse xenograft model of ALL with modern proteomic technologies provides a view of the leukaemia cell surface with an unprecedented resolution. A number of applications will be derived from this knowledge base. A significant contribution will be the identification of a new biologic subgroup in ALL that will provide new insights in disease pathogenesis and may be amenable to alternative, less toxic therapeutic approaches. PD Dr. Jean-Pierre Bourquin Abteilung Onkologie Kinderspital Zürich Universitäts-Kinderkliniken Steinwiesstrasse 75 CH-8032 Zürich Phone +41 (0)44 266 73 04 jean-pierre.bourquin@kispi.uzh.ch

Carbone Giuseppina Deregulated ETS transcriptional network and clinical implications for prostate cancer (KFS 02573-02-2010) Duration: 01.08.2010 01.08.2013 ETS transcription factors have emerged as important elements in the pathogenesis of prostate cancer, and chromosomal translocations involving ETS genes are very frequent. We recently showed that multiple ETS alterations coexist in prostate cancers, resulting in potential transcriptional and phenotypic synergistic effects that can influence the clinical behaviour of the tumour. Objectives In this application we plan to investigate the clinical and functional impact of aberrantly expressed ETS factors alone and in combination. We will evaluate ETS expression patterns at different stages of disease, the effects of deregulated ETS genes on the prostate cancer cell phenotype and transcriptome in vitro and in vivo and the impact of selected ETS factors and ETS target genes on tumour clinical behaviour. Methods To reach our goal, we will integrate data from clinical prostate cancer samples with molecular and functional studies in multiple ETS cell models. We will analyze patient samples from benign prostate from different stages of prostate cancer progression in archival formalin-fixed paraffin-embedded tissue specimens and in a large collection of tissue microarray (TMA). Correlation of ETS expression and clinical parameters will be also assessed. Potential patient benefit These studies will lead to a better understanding of the role of the ETS factors in prostate cancer initiation and progression and may have important implications for prevention, prognosis and treatment of this disease. Dr. Giuseppina Carbone Laboratorio di oncologia sperimentale Istituto oncologico della Svizzera italiana (IOSI) Via Vincenzo Vela 6 CH-6500 Bellinzona Phone +41 (0)91 820 03 66 Fax +41 (0)91 820 03 97 pina.carbone@irb.unisi.ch Cathomas Gieri The role of polyomavirus in the development of Merkel cell and epithelial skin carcinomas (KLS 02392-02-2009) Duration: 01.07.2009 01.07.2011 About 20 % of all malignant tumours are induced by infectious agents, namely, by viruses. Recently, a new virus called Merkel cell polyomavirus (MCV) has been detected in a rare aggressive skin tumour. We could show that MCV DNA can also be detected in about one-third of other epithelial skin tumours, tumours which are very common in the general population. In the present study, we are analyzing the type of MCV presence in these epithelial skin tumours using highly sensitive detection methods, including methods that allow the visualization of integrated virus within the cellular gene of the individual tumour cells. In addition, mutations in the viral genome will be analyzed, mutations which may be crucial for the malignant potential of this virus. The knowledge concerning tumour-inducing viruses is important, as contact with the virus can be omitted and a vaccine for prophylaxis may be developed. Prof. Dr. Gieri Cathomas Kantonales Institut für Pathologie Mühlemattstrasse 11 CH-4410 Liestal Phone +41 (0)61 925 26 21 Fax +41 (0)61 925 20 94 gieri.cathomas@ksli.ch Cavalli Franco A randomised phase II trial on primary chemotherapy with high-dose methotrexate (HD-MTX) and high-dose cytarabine (HD-AraC) with or without thiotepa and with or without rituximab, followed by brain irradiation vs. high-dose chemotherapy supported by autologous stem cells transplantation (ASCT) for immunocompetent patients with newly diagnosed primary central nervous system lymphoma (PCNSL) (KLS 02399-02-2009) Duration: 01.01.2009 01.01.2013 Still as of recently, there was practically no possibility of cure for patients with PCNSL. In the last years, results have improved, however. In an earlier study, the International Extranodal Lymphoma Study Group (IELSG) demonstrated that the combination of two cytotoxic agents (methotrexate with Ara-C) represents the best currently available treatment. In this study, this standard chemotherapy with or without the addition of thiotepa and rituximab is used in the induction treatment. Thereafter, patients are randomised in two different modalities of consolidation: either radiotherapy of the brain or highdose chemotherapy followed by reinfusion of autologous stem cells. The aim of the study is to further improve the outcome in the treatment of this lymphoma and concomitantly to clarify the role of the brain irradiation. Should it be possible in future to avoid this latter treatment, it would represent an important improvement, since patients could be spared a lot of side effects. Prof. Dr. Franco Cavalli Istituto oncologico della Svizzera italiana (IOSI) Ospedale San Giovanni CH-6500 Bellinzona Phone +41 (0)91 811 86 66 Fax +41 (0)91 922 20 84 franco.cavalli@eoc.ch Foti Michelangelo Role of dietary free fatty acids, microrna-21 and PTEN in liver cancer (KFS 02502-08-2009) Duration: 01.01.2010 01.01.2013 Diabetes and obesity represent important risk factors for the development of hepatocellular carcinoma (HCC). In particular, high levels of circulating fatty acids play an important role in the development of this cancer by stimulating an aberrant growth of hepatocytes. Fatty acids seem to act by inducing the expression of a specific microrna, mir-21, which inhibits the function of the tumour suppressor PTEN. 159

160 Our research projects aim at understanding the role of fatty acids, mir-21 and PTEN in the development of hepatic precancerous lesions and HCC. Experimental approaches using mouse genetic models fed special diets, and proteomic analyses to identify new factors modulated by mir-21/pten, are undertaken to reach this goal. Our research should allow us to better understand the molecular basis of liver cancer, in particular in the setting of metabolic diseases. In addition, the pertinence of future therapeutic interventions restoring normal mir-21 and PTEN activities in hepatocytes to prevent or treat liver cancer should also be evaluated. Dr Michelangelo Foti Département de physiologie cellulaire et métabolisme Centre médical universitaire (CMU) Faculté de médecine Université de Genève 1, rue Michel-Servet CH-1211 Genève 4 Phone +41 (0)22 379 52 04 Fax +41 (0)22 379 52 60 michelangelo.foti@unige.ch Gruber Günther BIG 3-07: A randomised phase III study of radiation doses and fractionation schedules for ductal carcinoma in situ (DCIS) of the breast (KFS 02527-02-2010) Duration: 01.02.2010 01.02.2013 Patients with ductal carcinoma in situ (DCIS) (precursor for breast cancer) are normally treated with breast-conserving surgery and postoperative radiotherapy (RT). This worldwide ongoing phase III trial is testing the influence of RT duration (different fractionation) and RT dose (+/ tumour bed boost) on local failure rates and quality of life (QoL). Aim of the study Individualization of postoperative RT for patients with DCIS after breast-conserving surgery for optimal tumour control and less toxicity. Methods Patients will be randomised into 4 treatment arms: 1) ARM A (25x whole breast RT) or 2) ARM B (16x whole breast RT) or 3) ARM C (ARM A + 8x boost) or 4) ARM D (ARM B + 8x boost). Clinical and biological parameters for local failure will be evaluated. QoL will be measured. Potential gain for the patients Radiotherapeutic individualization and optimization of different RT schemes in regard to local control and influence on QoL in patients with DCIS. PD Dr. Günther Gruber Institut für Radiotherapie Klinik Hirslanden Witellikerstrasse 40 CH-8032 Zürich Phone +41 (0)44 387 25 50 Fax +41 (0)44 387 25 51 guenther.gruber@hirslanden.ch Hegi Monika E. Targeting the EGFR/PI3K pathway in glioblastoma, what matters? (KFS 02670-08-2010) Duration: 01.02.2011 01.02.2014 Glioblastoma is the most aggressive and most common tumour of the brain, with a median survival of only 15 months despite modern therapies. New cancer drugs specifically target aberrantly modified or activated molecules in the tumour cells that are thought to be essential for aggressive growth and thus, may represent the molecular Achilles heel. We are investigating the regulatory network associated with the growth-promoting effect of the epidermal growth factor receptor (EGFR) that is highly amplified in 50 % of all glioblastoma. We will combine molecular data of glioblastoma tissue from patients treated with an inhibitor of the EGFR, with data from experimental investigations of the EGFR network in glioblastoma cell lines and mouse models. The aim is to identify critical molecular hubs of the network that need to be targeted for inactivation of its growthpromoting mechanisms. The goal is to propose effective combination therapies, adapted to the molecular makeup of glioblastoma. Prof. Dr Monika E. Hegi Laboratoire de biologie et génétique des tumeurs Service de neurochirurgie Centre hospitalier universitaire vaudois (CHUV) (BH19-110) Rue du Bugnon 46 CH-1011 Lausanne Phone +41 (0)21 314 25 82/81 Fax +41 (0)21 314 25 87 monika.hegi@chuv.ch Heim Markus Hermann Hepatocarcinogenesis in chronic hepatitis C (KLS 02552-02-2010) Duration: 01.07.2010 01.07.2012 Hepatocellular carcinoma is usually the consequence of chronic liver inflammation, for example chronic viral hepatitis C. The mechanisms responsible for carcinogenesis are not known. The aim of the study is to identify molecular mechanisms that are involved in hepatocarcinogenesis in chronic hepatitis C. We study liver cells that we infect with hepatitis C virus. We specifically investigate if important cellular processes such as DNA repair are impaired in cells infected with hepatitis C virus. We showed that an important phosphatase (PP2A) is induced by hepatitis C. PP2A inhibits another enzyme, PRMT1, which regulates histones through methylation of arginine amino acids. Histones are proteins that are important for the correct packaging of DNA in the nucleus. We plan to further investigate whether the changes induced by hepatitis C virus could be corrected by drugs such as S-adenosyl-L-methionine (SAMe) that correct the enzyme activity of PRMT1. Prof. Dr. Markus Hermann Heim Klinik für Gastroenterologie und Hepatologie Universitätsspital Basel Petersgraben 4 CH-4031 Basel Phone +41 (0)61 265 51 74 markus.heim@unibas.ch

Heinimann Karl mirna expression profiling in Lynch syndrome-associated colorectal cancer (KFS 2489-08-2009) Duration: 01.02.2010 01.02.2012 Colorectal cancer (CRC) is among the most common cancer types in the Western world. Up to 20 % of CRCs have a hereditary basis, with Lynch syndrome representing the most common cancer predisposition worldwide. Although the genetic basis of Lynch syndrome is well known, medical management of carriers remains difficult, in particular with regard to disease development, prognosis and cancer prevention. PD Dr. Karl Heinimann Forschungsgruppe Humangenetik Departement Biomedizin Universität Basel Mattenstrasse 28 CH-4058 Basel Phone +41 (0)61 267 07 73 karl.heinimann@unibas.ch Our study aims to assess how CRC development in Lynch syndrome is influenced by microrna (mirna) expression. mirnas are short RNA molecules that control about 30 % of all genes in man. Because of their diagnostic, prognostic and therapeutic potential, mirna research is topical. Our study wants to make a substantial contribution to the field, investigating a cohort of 260 clinically well-documented Lynch syndrome carriers and 145 CRC samples and comparing selected mirnas with their expression in sporadic colon cancer.

162 Körner Meike In vitro evaluation of the glucagonlike peptide 2 receptor expression in human cancer: Molecular basis for in vivo tumor radiotargeting (OCS 02349-02-2009) Duration: 01.07.2009 01.07.2011 Peptide receptors that are highly overexpressed in human tumours represent potential molecular targets for important clinical applications, namely, in vivo peptide receptor targeting of tumours. Radioactively labelled peptide analogues that bind specifically to tumoural receptors can be used for imaging or radiotherapy of tumours. Moreover, cold, long-acting peptide analogues may interfere with biologic functions of tumour cells regulated by peptide receptors, such as hormone release or proliferation. The glucagon-like peptide 2 (GLP-2) receptor represents a potential new candidate for such applications. It is closely related to the glucagon-like peptide 1 (GLP-1) receptor, which was recently identified as an important clinical target in insulinomas. The GLP-2 receptor had been of interest because of its stimulatory role in intestinal growth and, consequently, potential therapeutic use in short bowel syndrome. Lately, evidence has emerged on its possible role in cancer. The GLP-2 receptor was identified in tumours in single instances. Moreover, in vitro data indicate that it may stimulate tumour cell migration and growth. These preliminary results call for an in-depth evaluation of the GLP-2 receptor for its suitability as tumour target. The aim of our project was to perform the first step in that evaluation, namely, to assess the GLP-2 receptor expression quantitatively in a large spectrum of human tumours. We analyzed approximately 200 different human tissue samples for their GLP-2 receptor expression with in vitro receptor autoradiography. This method identifies receptor binding sites, i.e. the actual clinical target, in tissues. It allows specific receptor identification based on receptor pharmacology as well as quantification of receptor levels in tissues. We found a marked GLP-2 receptor expression in several tumour types mostly of gastrointestinal origin, in particular in gastrointestinal stromal tumours (GIST). The binding data were confirmed by RT-PCR. This tumoural GLP-2 receptor expression represents the molecular basis for an in vivo GLP-2 receptor targeting of GIST. In future studies it has to be investigated whether therapy with long-acting GLP-2 analogues of short bowel syndrome may affect the biologic behaviour of GIST. PD Dr. Meike Körner Abteilung für Zellbiologie und experimentelle Krebsforschung Institut für Pathologie Universität Bern Murtenstrasse 31 Postfach 62 CH-3010 Bern Phone +41 (0)31 632 99 60 Fax +41 (0)31 632 89 99 meike.koerner@pathology.unibe.ch Kristiansen Glen Identification of a clinically applicable prognostic RNA signature of prostate cancer (KFS 2465-08-2009) Duration: 01.01.2010 01.01.2012 A major problem in the treatment of prostate cancer relates to the difficulty in estimating tumour aggressiveness. This probably leads to over-treatment in up to 35 % of prostate cancer patients. Unfortunately, current clinical or histopathological approaches are still unsatisfactory with regard to predicting the aggressiveness of prostate cancer. The aim of our study is to develop and validate novel, mrna-based methods that will allow estimation of prostate cancer prognosis. In previous studies the applicant identified several mrna-based markers that are prognostically relevant. Modern high-throughput technologies allow their measurement simultaneously in many tumours. By comparing expression profiles in retrospective samples representing both aggressive and indolent tumours, combinations of markers or profiles will be developed that aid estimation of the risk of individual prostate cancers to progress and eventually lead to the patient s death or stay benign. In future, this approach may become an important tool for physicians that would allow them to apply tailored therapies to each patient based on a personal risk profile. Prof. Dr. Glen Kristiansen Institut für klinische Pathologie UniversitätsSpital Zürich Schmelzbergstrasse 12 CH-8091 Zürich Phone +41 (0)44 255 34 57 glen.kristiansen@usz.ch Mermod Nicolas Evaluation of AP2 protein-binding microarrays for breast tumor profiling and for the prognosis of the response to chemotherapies (KFS 02446-08-2009) Duration: 01.01.2010 01.01.2013 In Switzerland, about 5,000 new cases of breast cancer are recorded each year, and despite significant progress, about 1,500 patients still die of this pathology. This is a very heterogeneous disease whose accurate classification remains difficult. Although the diagnosis makes it possible to tailor treatment to individual cases, some tumours do not respond to the therapy, and it is generally difficult to predict with certainty whether a treatment will be effective for a given patient. With the ability to predict the lack of therapeutic response in case of neoadjuvant therapy (chemotherapy before surgery), unnecessary treatments could be avoided and the patient could be operated on without undue delays. Most molecular methods investigating tumour biology are exploring solely DNA, mrnas or proteins, and they are often unaware of the activity or functional interaction of proteins with each other and with target genes. In this project, we hope to develop an approach based on analyzing the interactions of proteins from the tumour with the genes responsible for tumour progression and resistance to chemotherapy, so as to provide a more comprehensive analysis of the tumour type and to potentially better predict its treatment response potential.

Study Objective To develop a new molecular diagnostic method to better predict the response to various therapeutic approaches available, especially focusing on neoadjuvant chemotherapy. Methods and Procedures Breast cancer chemotherapy resistance has been linked to the activity of transcription factor AP-2a, whose role in development and in various breast carcinogenesis has been well documented. However, the activity of AP-2a and its interaction with other oncogenic proteins are not easily detected by conventional techniques. This requires the establishment of innovative approaches to molecular diagnostics. Our previous results showed that a new approach based on the use of DNA chips called proteinbinding microarrays (PBM) allows detection of the activity and gene-binding specificity of the protein AP-2a from breast cancer biopsies and the distinguishing between healthy and cancer tissues. In this project proposal, we wish to use this technique to measure the activity of AP- 2a on a PBM covering 6,000 human gene sequences to identify molecular interaction signatures that may be indicative of the tumour resistance or sensitivity to chemotherapy. Potential benefits to patients The application of this technique to study the response to chemotherapy could lead to the development of a new predictive tool for the choice of the most appropriate treatment for each patient, according to the type of cancer, and thus to further increase the success of these therapies. Prof. Dr Nicolas Mermod Laboratoire de biotechnologie moléculaire Institut de biotechnologie Université de Lausanne CH-1015 Lausanne 15 Phone +41 (0)21 693 61 51 Fax +41 (0)21 693 76 10 nicolas.mermod@unil.ch Moeckli Raphaël Evaluation of second cancer risk models in radiotherapy for average and high dose levels (KFS 02637-08-2010) Duration: 01.01.2011 01.01.2013 Cancer survival rates have increased over the last decades due to improvement in treatment quality and earlier detection of the disease through screening programs. However, the price of this success is a higher probability of a radiation-induced second cancer later in life. Modern high-level radiotherapy techniques yield different types of dose distribution, which may have an impact on second cancer risk. Presently, the impact of these techniques on second cancer risk is not clear. The objective of this study is to better understand the impact on risk estimation of non-linear risk models applied to inhomogeneous dose distributions. Non-linear dose-risk models will first be applied in simple and well-known irradiation conditions. Then, the impact of realistic organ shape and size will be investigated. Finally, modern high-level treatment techniques will be investigated. The study will yield a better understanding of the response of non-linear risk models for different types of dose distributions. It will also give some insight into the discrepancies between different epidemiological studies in dose/risk estimations. Dr Raphaël Moeckli Institut de radiophysique Département de radiologie Centre hospitalier universitaire vaudois (CHUV) Rue du Grand-Pré 1 CH-1007 Lausanne Phone +41 (0)21 314 46 18 raphael.moeckli@chuv.ch Müller Beatrice U. Transcriptional dysregulation during myeloid transformation in acute myeloid leukemia (AML) (KFS-02449-08-2009) Duration: 01.01.2010 01.01.2013 Blood cancer, especially leukaemia, is a common disease, and improved therapeutic strategies are desperately needed, since the majority of patients with acute myeloid leukemia (AML) still die of their disease. In leukaemic cells, the normal development of white blood cells is typically blocked at a particular stage. In fact, blocked differentiation is the hallmark of acute leukaemia. Timely regulation of key transcription factors is crucial for normal haematopoiesis. In particular, the transcription factor CEBPA plays a key role in the differentiation of white blood cells. Disrupted CEBPA function leads to a block in differentiation at the myeloblast stage, whereas mature granulocytes are absent. Various alterations may lead ultimately to suppressed CEBPA function, thereby mediating the differentiation block in these leukaemias. What is missing so far is an unbiased comprehensive assessment of CEBPA transcription factor function among all subtypes of AML patients. Here we evaluate a method to reliably assess CEBPA function in AML patient samples at diagnosis. The hypothesis would be that suppressed CEBPA function is associated with favourable clinical outcome. We hope that this study will allow the identification of subgroups of AML patients that might benefit from therapeutic approaches targeting restoration of CEBPA function and thereby overcoming the differentiation block in these leukaemias. Dr. Beatrice U. Müller Departement für allgemeine Innere Medizin und klinische Forschung Inselspital CH-3010 Bern Phone +41 (0)31 632 03 78 Fax +41 (0)31 632 0514 beatrice.mueller@insel.ch 163

164 Nadal David Is endemic Burkitt s lymphoma really promoted by chronic innate immunity triggering by malaria infection? (KLS 02375-02-2009) Duration: 01.10.2009 01.10.2011 Endemic Burkitt s lymphoma (BL) is a type of lymph node cancer in Africa. The cancer cells harbour Epstein-Barr virus (EBV), which infects over 90 % of children for a lifetime. Malaria is thought to contribute to the formation of this cancer type. We have shown that stimulation of the innate immunity, as malaria does, pushes EBV into a form that enables lymphocytes to continuously proliferate. We will study the impact of immune stimulation on the preservation of EBV s form, leading to survival and unrestricted proliferation of cells. Newly gained insights into the interaction between chronic stimulation of the innate immunity and the behaviour of EBV-infected cells towards cancer will hopefully allow the engineering of novel modalities for prevention and treatment of EBV-harbouring lymphomas. Prof. Dr. David Nadal Abteilung Infektiologie und Spitalhygiene Kinderspital Zürich Universitäts-Kinderkliniken Steinwiesstrasse 75 CH-8032 Zürich Phone +41 (0)44 266 72 50 Fax +41 (0)44 266 80 72 david.nadal@kispi.uzh.ch Niggli Felix Constitution of a national study centre for the European acute lymphoblastic leukaemia trial (AIEOP-BFM ALL 2009) on behalf of the Swiss Paediatric Oncology Group (BFM-CH) (KLS 02578-02-2010) Duration: 01.06.2010 01.06.2013 Acute lymphoblastic leukaemia (ALL) is the most common malignancy of childhood. Remarkable progress has been made in the past decades. Combination treatment with intensive multi-agent chemotherapeutic regimens, adapted to biological factors like response to treatment, cytogenetic changes in leukaemic cells and minimal residual disease after initial treatment phase has raised the cure rate of the disease to over 80 %. However, treatment burden is still considerable. An international consortium established a new treatment protocol (AIEOP-BFM ALL 2009 trial) with risk adapted treatment application, taking also into account early response assessment. Within the Swiss Paediatric Oncology Group we will establish a national study centre for ALL to coordinate relevant diagnostic procedures and to perform reference investigation, data collection and coordination of research. We hope to further improve the survival rate for childhood ALL and to decrease side effects, at least in subgroups of patients. Prof. Dr. Felix Niggli Onkologielabor Kinderspital Zürich Universitäts-Kinderkliniken Steinwiesstrasse 75 CH-8032 Zürich Phone +41 (0)44 266 71 11 felix.niggli.@kispi.uzh.ch Ozsahin Hulya SIOPEL International Childhood Liver Tumour Strategy Group a comprehensive research program and a randomized trial for standard risk hepatoblastoma (KLS 02656-08-2010) Duration: 01.10.2010 01.10.2013 SIOPEL (Société internationale d oncologie pédiatrique Epithelial Liver Tumour Study Group) is a trials group for research on the diagnosis, treatment and long-term outcome of childhood hepatoblastoma (HB) and hepatocellular carcinoma. These cancers are extremely rare, with about 1.5 cases per million per year. The Swiss Paediatric Oncology Group (SPOG) has participated in SIOPEL trials 1 4 and is activating SIOPEL 6 in Switzerland. SIOPEL 6 is a multi-centre randomised phase III trial of the efficacy of sodium thiosulphate in reducing hearing loss with cisplatin chemotherapy for standard risk HB. The continued participation of SPOG in SIOPEL activities and research will result in optimal treatment of children with HB. Prof. Dr Hulya Ozsahin Unité d onco-hématologie pédiatrique Hôpitaux universitaires de Genève (HUG) 6, rue Willy-Donzé CH-1211 Genève 14 Phone +41 (0)22 382 46 20 Fax +41 (0)22 382 47 20 ayse.h.ozsahin@hcuge.ch Pabst Thomas Transcriptional dysregulation of the myeloid key transcription factor CEBPA in human acute myeloid leukemia (KLS 02520-02-2010) Duration: 01.07.2010 01.07.2013 Despite intensive chemotherapy, more than 50 % of patients with acute myeloid leukemia (AML) still die of the disease. To improve the treatment of patients with AML, novel innovative concepts are needed. The concept of differentiation therapy offers a possible approach. The block in normal differentiation of white blood cells is characteristic for AML cells. Importantly, each step during differentiation of normal white blood cells is regulated by only a handful of transcription factors. In particular, the transcription factor CEBPA plays a key role in this process. If CEBPA function is deficient, no mature granulocytes are observed, and this leads to an accumulation of leukaemic blasts. In this project, we analyze how CEBPA protein expression is regulated in leukaemic cells. Further, we aim to elucidate how CEBPA controls a new class of regulating molecules called micrornas. Through specific reconstitution of CEBPA function, we intend finally to develop a novel therapeutic approach for patients with AML. Prof. Dr. Thomas Pabst Institut für medizinische Onkologie Universität Bern Inselspital CH-3010 Bern Phone +41 (0)31 632 41 15 Fax +41 (0)31 632 41 19 thomas.pabst@insel.ch

Petignat Patrick Self-sampling for HPV in women who do not undergo routine cervical cancer screening: A randomized trial (KFS 02691-08-2010) Duration: 01.09.2011 01.09.2013 In Switzerland, 250 to 300 women are diagnosed with cervical cancer each year, and 100 die of the disease. Some 30 40 % of Swiss women do not have cervical cancer screening and are therefore at higher risk of developing cervical cancer. The study will include 1,100 women aged 25 to 69 years who have not participated in routine screening in the last three years. They will be invited to the screening procedure, a Pap smear (control group), or HPV self-sampling (study group). In the latter group, women will be able to take the sample themselves at home, using a kit that will be sent to them. The results of this study could provide women not screened by Pap tests with a simple alternative form of screening. This could overcome barriers to presentation for screening, such as difficulty in reaching a doctor, reluctance to undergo gynaecological examination and cost. Interviews will be conducted in order to gain a better understanding of the reasons for non-attendance and to gauge the acceptability of self-sampling. Prof. Dr Patrick Petignat Unité d oncogynécologie chirurgicale Hôpitaux universitaires de Genève (HUG) Boulevard de la Cluse 30 CH-1211 Genève Phone +41 (0)22 382 68 16 patrick.petignat@hcuge.ch Renevey Philippe Automatic vocal aid system for laryngectomees with improved voice quality (KFS 02681-08-2010) Duration: 01.01.2011 01.01.2013 Medical rehabilitation techniques allow laryngectomees to partially recover vocal function, but it results in poor voice quality and insufficient speech intensity. The ultimate goal of the project is the improvement of existing speech processing algorithms for laryngectomees, which would increase laryngectomees quality of life by improving their communicational abilities. The approach is to further improve and refine the algorithms for speech restoration developed in a previous project. Special attention will be devoted to enhancing the perceived natural characteristics and speaker-specific artefacts. High perceptual performance will be aimed at, such as improving speech quality and intelligibility, through combined state-of-the-art parametric and statistical signal processing methods. The expected result is to obtain a sufficient quality of the restored speech so as to be integrated in a usable system (e. g. vocal aid, improvement of telephone calls, public audience amplification). Dr Philippe Renevey Centre suisse d électronique et de microtechnique (CSEM) Rue Jaquet-Droz 1 CH-2007 Neuchâtel Phone +41 (0)32 720 55 27 prv@csem.ch Resink Therese T-cadherin: a functional determinant and early prognostic marker for malignant transformation of squamous cell carcinomas (KFS 02447-08-2009) Duration: 01.01.2010 01.01.2013 Skin cancer is a disease in which cancer cells are found in the outer layers of the skin. It occurs in different forms. Melanoma is highly metastatic and deadly. Basalioma (basal cell carcinoma) and spinalioma (squamous cell carcinoma) are relatively benign, but they occur much more frequently and cause major disfigurement. Whereas basalioma growth is locally restricted, spinalioma can transform into malignant metastatic cancers with fatal results. We want to understand the whys and hows of this transformation, and focus on T-cadherin, a molecule that seems important for integrity of skin. Too much or too little of T-cadherin has been found in many skin diseases, including skin cancers. We are studying tissue from spinalioma patients to see if particular changes in T-cadherin can predict malignant transformation. We use cells isolated from healthy skin and spinalioma to study how changes in T-cadherin affects growth and metastatic potential. Given that Switzerland has one of the highest rates of skin cancers in Europe, our results will aid better identification and treatment of those patients at risk of developing metastatic spinalioma. Prof. Dr. Therese Resink Forschungsgruppe Signaltransduktion Departement Biomedizin Universitätsspital Basel Hebelstrasse 20 CH-4031 Basel Phone +41 (0)61 265 24 22 therese-j.resink@unibas.ch Roth Arnaud Molecular heterogeneity and prognostic markers in colon cancer by analysis of gene expression and gene mutation data (KFS 02697-08-2010) Duration: 01.01.2011 01.01.2013 Prognostic markers allowing better determination of which patients operated on for colon cancer could benefit from additional treatment are missing. PETACC-3, a clinical trial in postoperative treatment of colon cancer, enrolled 3,278 patients and collected the pathologic material of 1,564 of them for the study of new molecular prognostic factors. In addition to the ability to validate some already known potential prognostic molecular markers, we performed new tests to insulate mutations of the genome of the tumour and to study their genomic expression. These tests provided us with large sets of data 165

166 (> 50.000/patient). For their analysis, the Swiss Group for Clinical Cancer Research (SAKK) obtained the assistance of the Swiss Institute of Bioinformatics (SIB), which is specialized in the analysis of this type of biological data, with the financial support of the Swiss Cancer League. Dr Arnaud Roth Unité d oncochirurgie Hôpitaux universitaires de Genève (HUG) 4, rue Gabrielle-Perret-Gentil 1211 Genève 14 Phone +41 (0)22 372 77 44 Fax +41 (0)22 372 98 50 arnaud.roth@hcuge.ch Rothermundt Christian Metformin in castration resistant prostate cancer. A multicenter phase II trial of the SAKK (Swiss Group for Clinical Cancer Research) (SAKK08/09) (KFS 02641-08-2010) Duration: 01.01.2011 01.07.2012 Patients with prostate cancer receiving androgen deprivation therapy (orchiectomy or GnRH analogue) develop hyperglycaemia and hyperinsulinaemia. There is a suggestion that high insulin concentrations promote progression of prostate cancer. Metformin is a biguanide and is being used in the treatment for diabetes. Metformin can potentially revert the above-mentioned negative effects of androgen deprivation in patients with metastatic prostate cancer. Additionally, metformin has an inhibitory effect on cell proliferation. We conduct a multicenter phase II trial with metformin in patients with slowly progressing castration resistant prostate cancer. The research question is whether metformin can stabilize the disease with tolerable side effects. We also measure metabolic changes due to metformin, and we aim to identify pharmacogenetic markers for a favourable treatment response. Dr. Christian Rothermundt Fachbereich Onkologie/Hämatologie Kantonsspital St. Gallen CH-9007 St. Gallen Phone +41 (0)71 494 11 63 christian.rothermundt@kssg.ch Rufer Nathalie Structural and functional studies of T-cell receptors specific for tumor antigens: Implications for immunotherapy of cancer patients (KLS 02635-08-2010) Duration: 01.04.2011 01.04.2013 Although tumour-reactive T lymphocytes can be detected in cancer patients, these immune responses often fail to control or eliminate the disease. Adoptive transfer of T- cells engineered with T-cell receptors (TCRs) has been recently developed with the aim to induce immune reactivity towards defined tumour-associated antigens to which the endogenous T-cell repertoire is non-responsive. An attractive approach to improve this strategy is to optimize the TCR sequence to increase its affinity for cognate tumour antigen. We recently generated tumour-specific T lymphocytes expressing sequence-optimized TCRs, and we showed that T-cell immune responses against cancer cells could be specifically improved. However, our study also revealed the presence of an affinity window for optimal T-cell function. The objectives of our current project are to characterize some of the parameters involved in regulation of TCR function. Identifying rationally optimized TCRs and expressing such tumour-specific receptors in T lymphocytes represents one of the most promising approaches to improving adoptive T-cell therapy against cancer. Dr Nathalie Rufer Centre Ludwig de recherche sur le cancer Université de Lausanne c/o CHUV HO 05/1532 Avenue Pierre-Decker 4 CH-1011 Lausanne Phone +41 (0)21 314 01 99 nathalie.rufer@unil.ch Schwaller Jürg Exploring new molecular therapeutic targets in MLL-X acute leukemia (OCS 02357-02-2009) Duration: 01.07.2009 01.07.2011 Expression of mixed lineage leukaemia/lymphoma fusions (MLL-X) is a hallmark for a significant group of paediatric, adult and therapy-related acute leukaemias with a poor prognosis. Previous work suggested that the MLL fusion is essential to induce and probably maintain the disease. Genetic studies identified potential functional co-factors as well as downstream effectors of MLL-X leukaemogenesis including protein kinases like PIM1. We propose to: 1) address the role of PIM kinases as biomarkers and therapeutic targets in haematological malignancies including MLL leukaemia; 2) search for potentially druggable novel protein kinases by performing an RNA interference screen in cells from conditional transgenic MLL models; and 3) to explore possibilities to block MLL leukaemia by targeting the fusion or critical co-factors of the MLL-X complex. Our project will provide important insights for potential molecular targeting, setting new landmarks for future therapeutic intervention. Prof. Dr. Jürg Schwaller Forschungsgruppe Kinder-Leukämie Departement Biomedizin Universitätsspital Basel Hebelstrasse 20 CH-4031 Basel Phone +41 (0)61 265 35 04 Fax +41 (0)61 265 23 50 j.schwaller@unibas.ch

Skoda Radek C. The pathogenesis of myeloproliferative disorders (KLS 02398-02-2009) Duration: 01.10.2009 01.10.2012 Myeloproliferative disorders (MPD) are chronic blood diseases characterized by overproduction of blood cell precursors in the bone marrow. Patients with MPD bear an increased risk (5 20 %) to develop an acute leukaemia after a variable latency. Therefore, MPD is often considered a pre-leukaemia. We found that in about 70 80 % of MPD patients, the blood stem cells carry a mutation in the gene Janus kinase 2 (JAK2). JAK2 is an enzyme that transmits signals coming from the outside into the cell and the mutation (JAK2-V617) amplifies the growth-promoting effect of these signals, so that more blood cells are formed. The aim of our studies is to better understand how the JAK2-V617F mutation causes MPD, with which partner genes it collaborates in this process and what the predisposing events are that can favour the acquisition of MPD. To address these questions, we are combining detailed analysis of cells and tissues from patients with MPD with mouse models of MPD. Our studies in patients revealed that JAK2-V617F may be preceded by as yet unknown mutations. To follow up on this observation, we studied patients with MPD that in addition to JAK2-V617F have deletions of chromosome 20q (del20q) or carry mutations in a gene called TET2, and we determined the temporal order in which these mutations were acquired. Our studies showed that there is no fixed order of events, and some patients acquire JAK2-V617F first, followed by del20q or TET2 mutations, whereas in other patients with MPD the inverse order can be observed. Thus, deletions of chromosome 20 and mutations in TET2 are unlikely to represent pre-disposing events for JAK2-V617F, and we are examining other candidate genes for such a function in familial forms of MPD. A second question that we are addressing is why the JAK2-V617F mutation can cause 3 different subtypes of MPD, namely, essential thrombocythemia (ET) with elevated platelet levels, polycythemia vera (PV) with increased numbers of red cells and in some cases primary myelofibrosis (PMF) with fibrosis of the bone marrow and blood formation in the spleen and liver. We generated a mouse model of MPD that expresses the mutant JAK2- V617F and displays all 3 types of MPD. We found that ET develops when the mutant human JAK2-V617F is expressed at lower levels, while at higher levels PV phenotype can be observed. Myelofibrosis occurred later in these mice and appears to correlate with the platelet counts. Interestingly, when we made a mutation in a different position in JAK2 that is associated with a pure red cell phenotype in patients (JAK2 exon 12 mutation), we observed a pure red cell elevation in the mice, i.e. the same phenotype as in patients. Thus, in addition to expression levels, the different JAK2 mutations may also cause different quality of signals that favour the expansion of specific blood cell types. Finally, inhibitors have been developed that can reduce the enzymatic activity of JAK2 and are undergoing clinical trials in patients with MPD. Our mouse models have proven to be valuable in testing such compounds. Our projects on JAK2 have contributed to changing the diagnostic and therapeutic approach to patients with MPD. We are now examining how other known gene mutations collaborate with JAK2 mutations and are searching for as yet unknown new gene mutations in MPD. Prof. Dr. Radek C. Skoda Forschungsgruppe experimentelle Hämatologie Departement Biochemie Universitätsspital Basel Hebelstrasse 20 4031 Basel Phone +41 (0)61 265 22 72 Fax +41 (0)61 265 32 72 radek.skoda@unibas.ch Stenner-Liewen Frank Establishment of GOLPH2 as a serum marker in hepatocellular carcinoma (within the SAKK 77/08 trial) and in bile duct cancer for routine clinical use (KFS 02423-04-2009) Duration: 01.11.2009 01.11.2011 Malignant tumours of the liver are often detected in advanced stages, thus having a poor prognosis. Strategies for detection and surveillance of hepatocellular carcinoma (HCC) are urgently warranted. We recently described a novel marker GOLPH2 in HCC and bile duct cancer (BDC). Validation of our data and meanwhile other conformational data will be validated prospectively within the setting of a randomised clinical trial. Purpose Within the HCC trial SAKK 77/08 serial GOLPH2 measurements will be performed to investigate the prognostic and predictive value of this tumour marker. Methods Serum-GOLPH2 will be quantified using a sandwich ELISA, or enzyme-linked immunosorbent assay. Specific antibodies against GOLPH2 and purified GOLPH2 will be employed. Further, by screening phage libraries novel antibodies for therapeutic and testing purposes will be defined. Descriptive statistical analysis will be performed correlating GOLPH2 values with disease progression and overall survival. Benefit for patients A new marker for diagnostics and monitoring of HCC and BDC could be established. This has the potential to simplify clinical routine and clinical trials. PD Dr. Frank Stenner-Liewen Medizinische Onkologie UniversitätsSpital Zürich Rämistrasse 100 CH-8091 Zürich Phone +41 (0)44 255 22 14 Fax +41 (0)44 255 45 48 frank.stenner@usz.ch 167

Zeller Rolf Functional analysis of modulators of SHH pathway activity during the formation of medulloblastomas: A mechanistic study with clinical relevance (OCS 02368-02-2009) Duration: 01.01.2010 01.01.2013 168 Medulloblastomas are among the most common and aggressive childhood brain tumours. Currently, the only therapy involves surgery in combination with radio- and chemotherapy. However, this often results in long-term negative side effects, as postnatal brain development is not yet completed at the time of treatment. The mechanisms underlying medulloblastoma development are analyzed using Ptch1 heterozygous mice, which are an excellent animal model. We showed that the protease inhibitor PN-1 is upregulated in 95 % of all biopsies of human medulloblastoma patients and overexpressed in mouse medulloblastomas. Genetic reduction of PN-1 in the mouse model reduces the tumour frequency by about two-thirds, and the remaining medulloblastomas are less aggressive. Therefore, we hope that our studies will not only provide insights into tumour formation but also pave the way to molecular therapy strategies of medulloblastomas. Prof. Dr. Rolf Zeller Forschungsgruppe Entwicklungsgenetik Departement Biomedizin Universität Basel Mattenstrasse 28 CH-4058 Basel Phone +41 (61) 695 30 33 Fax +41 (0)61 695 30 90 rolf.zeller@unibas.ch

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Psychosocial research 171 Palliative care research in Switzerland The National Strategy for Palliative Care 2010 2012 [1] declared the promotion of research in the field of palliative care an urgent task. This prioritization is correct and important. Each year the European Association for Palliative Care (EAPC) holds a World Research Congress, at which important research activities in all European countries and also other countries are presented. Switzerland has been a participant at the congress for many years; however, it is worth noting that the same group of people present their work year after year. This indicates that Switzerland has unfortunately not succeeded in significantly strengthening and expanding this group of researchers. In international comparison, it is also noticeable that most of the research on palliative care in Switzerland is in the medical area, with clearly fewer studies being conducted in the areas of care, sociology, public health, and psychology. Current topics in palliative care research in Switzerland The working group for research of the Schweizerische Gesellschaft für Palliative Medizin, Pflege und Begleitung (abbreviated as palliative ch ) lists the current research focal points in Switzerland [2]: end of life issues, including decision-making processes and patients living wills, care of the dying, palliative aspects, and aspects of assisted suicide. In addition, there is a lot of research activity in the area of frequent symptoms, especially fatigue, significant weight loss, and pain, and there are some projects on specific topics in the areas of neurology, cardiology, intensive care, paediatrics, and different types of dementia. Much less research activity is found in the Steffen Eychmüller, MD Medical director and head of the Center for Palliative Care at the Cantonal Hospital of St. Gallen

172 area of health services research. 1 This is mostly due to the fact that with the health system organized by the cantons, making it difficult to track patients paths, there are definite limitations to conducting this kind of research in Switzerland. Countries with national health systems are much more active in such areas of research. Regarding patient groups, the research activities on patients diagnosed with cancer continue to be the most frequent. This accords only in part with the international trend. In recent years, other countries have put much more emphasis on integrating patient groups with cardiovascular disease and pulmonary disease, and research interest has also focused on neurological diseases and especially dementia. Based on the World Health Organization s definition of palliative care [3] it follows that palliative care research should not be restricted to medical issues but should instead include research topics from other areas, such as ethics, sociology, and economics. But the non-medical area has been underrepresented in the research up to now. However, there is hope that this will change through the National Research Programme End of Life (NRP 67), which was launched in 2011 and covers a wide range of topics. Attractiveness of palliative care research, especially for junior scientists In the field of palliative care, there is a demand for research projects that are highly practice-oriented and need-oriented. Researchers are supposed to give greater heed to the soft voice of the seriously ill and dying and their caregivers. The idea of bottom-up or grassroots research impresses people, but it is not usually feasible in practice. Due to a lack of time and a lack of research resources, specialists working in clinical practice are often hardly in a position to submit research proposals that have a chance of being approved for a grant and to conduct research. Partners in academia as engines are urgently needed here and could, at least theoretically, join with specialists to become successful duos of practical orientation and academic competency and to be brilliant in a joint effort. With regard to these prospects, Switzerland has definitely fallen behind in international comparison. So far, there has been only one single chair in palliative care at the universities (an endowed chair at the University of Lausanne), and for years, no one could be appointed to it. At present, no further professorships are foreseen. At the universities of applied sciences, too, there are no specialized institutes or specialists for research in palliative care focusing on research topics in this field. In the professional curricula, in particular in medicine and nursing, there are still no specialized programmes leading to nationally recognized titles. But in the end, this type of specialized postgraduate 1 Health services research is a research area within health care system research at the microlevel of the health care system, in particular hospitals, doctors practices, or specific technologies in the health system. The subject of health services research is sickness and wellness services. Other factors, such as the intermediary institutions (health insurance companies, medical associations, etc.) and the national health policy that shapes services in the long term are not the direct subjects of research. But they are taken into consideration in the scientific studies as framework conditions of certain health services.

programme is needed not only to interest young specialists in a new field but also to offer them attractive professional development. Ultimately, in view of the definition of palliative care, it would be important to set up inter-professional professorships, such as a joint academic position for persons in nursing and medicine, or also in public health and other areas. They would then collaborate on the broad and varied spectrum of palliative care and promote joint research. Palliative care research in different language regions of Switzerland When embarking upon a new field of study (such as research in the field of palliative care), it is an advantage when it can be done in one s native language. Trying to understand the research methodology and dealing with statistics and research designs works best when one thoroughly understands the contents. For this reason, English as the research language is not always appropriate, and it is very understandable that members from the different language regions of Switzerland are joining together for these first steps in palliative care research. For instance, the Plateforme latine de recherche en soins palliatifs et fin de vie (www.plrsp.ch) was established in 2010. In an exemplary manner, this platform not only brings together researchers at different academic institutions but also, and most importantly, people interested in research at institutions in clinical practice, from hospitals to Spitex home care to nursing homes. This is a first step: not only to overcome barriers between academic institutions and the world of clinical practice and patient care but also as the researchers attempt to communicate together in their own language efficiently and understandably. The Plateforme latine de recherche for the French-speaking region of Switzerland is also open to Italian-speaking colleagues in Ticino. A similar platform is planned to be established for the German-speaking region of Switzerland in September 2011. International cooperation Another way to strengthen the national research capacity in the field of palliative care is to co-operate with international partners. Here in Switzerland, we already have many contacts. They range from the Euro-Sentinella collaboration between the Swiss Sentinel Surveillance Network (general practitioners) and European countries to cooperation with the University of Ottawa in Canada (Lausanne), but there are also contacts within EU projects. Here, in particular two projects in St Gallen, EPCRC and OPCARE9, profited greatly and have expanded their own research capacities in recent years [4, 5]. In the European Palliative Care Research Collaborative (EPCRC), research topics such as genetic disposition and the administering of opiates were examined. In Optimizing Care of the Dying in 9 Countries (OP CARE9), the aim was to set up a research collaboration on events in the dying process and their effects on support, monitoring, and treatment. These projects, funded through the EU 7 th Framework are lucky chances, since they boost intensive collaboration with clear objectives and capacity building for several years to come. At the international level, this has led to additional projects. Furthermore, it has become clear that if palliative care research in Switzerland does not become firmly anchored in the academic sector, it is unlikely to remain competitive in the future. The phase of pioneers, also in research, must now become consolidated through a phase of implementation and integration of palliative care in the national research landscape. This is the only way that Switzerland s continued participation in larger international projects with considerable potential synergies for national research can be ensured. 173

174 The financing of palliative care research in Switzerland In my experience, the pioneering phase is also over with regard to funding. In past years, first research projects could still find financial support outside of competitive research funds, based on goodwill. Now, this has clearly changed. Our research projects in all areas must bear critical evaluation in the form of the internationally established and common peer review system. With respect to quality, this is surely welcomed, but on the other hand, there are few reviewers who know and recognize the specific aspects of palliative care, from its inter-professional nature to multidisciplinarity and the specific methodology and its restrictions in the research. Special funding programmes could be an important step here. Another issue concerns the extent to which private foundations show commitment and interest in this much neglected area of research. In 2009 the Council of Europe adopted a resolution on palliative care, assessing palliative care as a model for innovative health and social policies [6]. This could and should also serve as a model for the future development of palliative care research in Switzerland: an innovative model for inter-professional research and research in the related areas of health system, sociology, public health, economics, ethics, philosophy, and many other areas. With regard to the broad orientation of this research, the National Research Programme End of Life (NRP 67), launched in 2011, is a significant milestone. It remains to be seen whether this measure will suffice to firmly anchor this wide range of research in Switzerland. What is palliative care? Palliative care is the care and treatment of persons with terminal, life-threatening and/or chronic, progressive illnesses. Palliative care begins early on, but its main emphasis is during the time when curing the disease is no longer considered possible and is therefore no longer the primary objective. Patients are ensured an optimal quality of life, adapted to their situation, up to the end of life, and their loved ones are offered appropriate support. Palliative care prevents suffering and complications. It encompasses medical pain and symptom relief and psychological, social, and spiritual support [7].

Conclusion Palliative care is a broad and an interesting topic. In the light of the sociodemographic development in Switzerland and other Western countries, the social and political relevance of palliative care research is very high. Research efforts show that results cannot simply be imported from elsewhere but instead must be adapted to the cultural context of a country, or must be gained in the country itself. For this reason, an important objective over the years to come will be the establishment of a broad research community in the field of palliative care in Switzerland. This should represent and revitalize the various axes: from clinical practice research to philosophical issues, from various regional foci in the sense of a virtual national research institute to international collaboration and all of this supported and solidly anchored within the academic world. This objective could best be reached in Switzerland by establishing modern, inter-professional professorships in palliative care. In this way, palliative care could be further developed as an innovative model also in research. Steffen Eychmüller, MD Steffen Eychmüller has been medical director and head of the Center for Palliative Care at the Cantonal Hospital of St Gallen since 2006. He studied medicine and completed his residency in Germany and Switzerland. He then conducted research in Sydney and Perth, Australia. Eychmüller specializes in palliative care, psycho-oncology, and pain. He is a co-investigator in the European research project OPCARE9. From 2005 to 2009 he was co-president of the Schweizerische Gesellschaft für Palliative Medizin, Pflege und Begleitung (palliative ch). Phone +41 (0)71 494 35 51 steffen.eychmueller@kssg.ch www.palliativ-sg.ch References 1. BAG/GDK (Federal Office of Public Health/Swiss Conference of the Cantonal Ministers of Public Health). Nationale Strategie Palliative Care 2010 2012 [National Strategy for Palliative Care 2010 2012]. Available in German, French, and Italian at www.bag.admin.ch/palliativecare. A summary in English is available at http://www.bag.admin.ch/ themen/medizin/06082/10907/index.html?lang=de 2. palliative ch working group for research (Arbeitsgruppe Forschung): www.palliative.ch/index. php?id=126 3. WHO Definition of Palliative Care (2002): www.who.int/cancer/palliative/definition/en/ 4. European Palliative Care Research Collaborative EPCRC: www.epcrc.org 5. OPCARE9, a European collaboration to improve care of the dying: www.opcare9.eu 6. Council of Europe Resolution 1649 (2009): Palliative care: a model for innovative health and social policies: http://assembly.coe.int/mainf.asp?link=/documents/ AdoptedText/ta09/ERES1649.htm 7. BAG/GDK (Federal Office of Public Health/ Swiss Conference of the Cantonal Ministers of Public Health). (2010). Nationale Leitlinien Palliative Care [National guidelines for palliative care] (p. 8). Bern: BAG/GDK. 175

National Strategy for Palliative Care 2010 2012 The number of deaths per year in Switzerland will increase in the coming years and decades. Today, 60,000 persons of all ages die each year in Switzerland. The Federal Statistical Office (FSO) expects the number to reach 90,000 persons annually by the year 2050. This is due mainly to the age structure of the population: Predictions show that by 2030 the number of persons over the age of 80 will more than double. In addition, owing to the rising life expectancy and medical advances, chronic illnesses and multimorbidity when persons have several concurrent chronic conditions have become more frequent. This affects not only older persons but also younger, seriously ill patients with cancer, neurological disorders or chronic, progressive diseases. 176 A future consequence of this development is that, for one, the need for extensive care and treatment in the final phase of life will be greater. For another, medical care and treatment will become significantly more complex. In view of these diverse societal, social and health policy challenges, the Swiss government and the cantons decided to join together to promote palliative care in Switzerland. To this end, in the context of the National Health Policy Dialogue platform they launched the National Strategy for Palliative Care 2010 2012. With the National Strategy, the Confederation and the cantons established goals towards closing the identified gaps in access to care, financing, awareness, training and research. The measures will be realized and the means used in a targeted-oriented way in a concerted effort by all partners. The National Strategy focuses on increased coordination and on better utilization of synergies at the national and cantonal levels. Palliative care is the care and treatment of persons with terminal, life-threatening and/or chronic, progressive illnesses. Palliative care begins early on, but its main emphasis is the time when curing the condition is no longer considered possible and is no longer the primary goal. The goal of the National Strategy for Palliative Care is to allow all chronically ill and dying persons to receive palliative care that is adapted to their situation in order to improve their quality of life. Federal Office of Public Health (FOPH) Health Policy Directorate Daniela Wäfler Head, National Strategy for Palliative Care P. O. Box CH-3003 Bern Phone +41 (0)31 325 52 53 palliativecare@bag.admin.ch www.bag.admin.ch/palliativecare

National Research Programme End of Life (NRP 67) The NRP 67 End of life aims to gain new insights into the last phase of life. The knowledge useful to guiding decisions and practices during the last stage of life will be made available to decision-makers in the health care system, as well as to politicians and professionals involved in the care of persons at the end of life. Persons at the end of life refers to persons whether newborn infants, children, young people, middle-aged, elderly or very elderly people who in all likelihood will live no more than a few months. Perceptions and frameworks regarding the end of life in a state of flux Perceptions and frameworks regarding the end of life are currently in a state of flux. New institutions, such as palliative care services or suicide assistance organizations, dedicate themselves to the needs of persons reaching the end of life. Demographic changes and new forms of family life challenge traditional models for support and provision of care to persons at the end of life. Living wills, the practice of suicide assistance, diverse expectations towards medical care, and high health care costs, have become the subject of heated public debate. 177 Most people in Switzerland currently die in old age. Medical decisions influence the dying process in many cases. The focus of these decisions is to ensure a good dying, and no (longer) to fight impending death. The discourse on good and bad dying has become increasingly pluralistic and intense in recent years. Better understanding of dying processes New research is needed to understand these developments better. This is the rationale for NRP 67, which includes four main research areas: Dying processes and provision of care: The focus here is on the current state of care for persons at the end of life in Switzerland, on dying processes, and on attendant practices with a special focus on palliative care. Decisions, motives and attitudes: This area centres on decisions made during the dying process, and on the motives, convictions and attitudes underlying them. Regulations and proposals for action: The focus here is on normative rules such as legal regulation or ethics guidelines, as well as questions regarding distributive justice in the health system. Cultural concepts and social ideals: Death and dying have attracted a great deal of public interest in recent years. This research area includes questions regarding how death and dying are given meaning, cultural representations of death and dying, and relevant social normalization processes. In February the Federal Council commissioned the Swiss National Science Foundation to carry out NRP 67 End of life. This research programme is endowed with a budget of CHF 15 million. The research projects will be selected after a two-stage procedure in 2011. The research projects will start in spring 2012 and will be completed in 2017. NRP 67 End of life Dr. Stephanie Schönholzer Swiss National Science Foundation Wildhainweg 3 3001 Bern Phone +41 (0)31 308 22 22 Fax +41 (0)31 305 29 70 sschoenholzer@snf.ch www.nfp67.ch

Psychosocial research List of completed research projects from July 2008 to December 2010 Ansermet François KLS 01705-04-2005 CHF 273,000. Service de psychiatrie de l enfant et de l adolescent (SPEA), Hôpitaux universitaires de Genève (HUG), Genève Biobehavioral responses to stress in adult survivors of a childhood cancer Eychmüller Steffen OCS 01776-08-2005 CHF 170,000. Palliativzentrum, Kantonsspital St. Gallen, St. Gallen Palliative care services in Switzerland: From a national survey to the development of a specific monitoring instrument 178 Kiss Alexander KLS 02038-02-2007 CHF 302,000. Abteilung Psychosomatik, Departement Innere Medizin, Universitätsspital Basel, Basel Physical and psychological predictors of patient fatigue 1 to 10 years after human stem cell transplantation Lehr Hans-Anton OCS 02209-02-2008 CHF 240,400. Institut universitaire de pathologie de Lausanne (IUP), Centre hospitalier universitaire vaudois (CHUV), Lausanne Biomedical research on human tissues: In the twilight zone between autonomy and data protection. What do health professionals, patients and lay persons think about issues of consent and transparency in medical research, teaching, and quality control? Rüesch Peter KLS 02198-02-2008 CHF 155,800. Fachstelle Gesundheitswissenschaften, Departement für Gesundheit, Zürcher Hochschule für Angewandte Wissenschaften (ZHAW), Winterthur Information needs of patients with curable adenocarcinoma of the prostate and professionals opinions: An international study (INEPAP) Schulz Peter J. OCS 02101-08-2007 CHF 150,400. Istituto di comunicazione e sanità, Università della Svizzera italiana, Lugano Cancer and health literacy: Establishing a concept of cancer literacy Schwappach David OCS 02109-08-2007 CHF 117,200. Stiftung für Patientensicherheit, Zürich Involving chemotherapy patients in the prevention of medical errors a feasibility study Stiefel Friedrich OCS 01847-02-2006 CHF 184,600. Service de psychiatrie de liaison (PLI), Centre hospitalier universitaire vaudois (CHUV), Lausanne Evaluation of individual and group psychotherapy for emotionally distressed cancer patients: A randomized controlled trial Stiefel Friedrich KLS 02035-02-2007 CHF 126,300. Service de psychiatrie de liaison (PLI), Centre hospitalier universitaire vaudois (CHUV), Lausanne Effects of communication skills training on oncology clinicians communication styles and defense mechanisms von der Weid Nicolas KLS 02215-02-2008 CHF 285,900. Service de pédiatrie, Centre hospitalier universitaire vaudois (CHUV), Lausanne Long-term outcome of childhood cancer: Incidence and spectrum of late effects Znoj Hansjörg OCS 01741-08-2005 CHF 104,800. Abteilung klinische Psychologie und Psychotherapie, Institut für Psychologie, Universität Bern, Bern Posttraumatic personal growth and posttraumatic stress in patients and their partners adapting to cancer

Psychosocial research Presentation of completed research projects from July 2008 to December 2010 Eychmüller Steffen Palliative care services in Switzerland: From a national survey to the development of a specific monitoring instrument (OCS 01776-08-2005) Purpose In terms of end of life care, Switzerland is known for its legalization of physician-assisted suicide but less for excellence in palliative care. This study provides the results of a national survey on the current situation of palliative care in the country. Method We conducted a national survey on all hospitals, residential aged care facilities and cancer networks and on a sample of community nursing services stratified by canton, addressing the institutions directors/head-nurses. Results In total 2,115 surveys were distributed. Response rate was 57 % (n=1195), with an equal distribution from all care settings all over Switzerland. The overall image of palliative care is positive and largely integrated in conceptual frameworks, but there is no common definition of service characteristics (i. e. for specialist palliative care services), and implementation in daily practice varies widely. Geographically, the distribution of specialist palliative care services shows a predominance of the French-speaking part of Switzerland. Use of specific palliative care assessment tools or guidelines is best within hospital settings. Composition and training of specialist palliative care teams in most of the settings may not reach international standards. As part of the project, a minimal data set for patients in specialist palliative care settings was piloted in 2008 and presented during the national consensus conference for palliative care in December 2008. Conclusion Palliative care is poorly developed in Switzerland with regionally few exceptions due to historic factors. A national strategy has been adopted only recently. Recommendations for the future This national survey was used as a major starting point to be built on for the National Strategy for Palliative Care 2010 2012 as published at the end of 2009. In addition, a first edition of a Swiss Palliative Care Directory was published in 2008, followed by a second version planned for spring 2011. A national dataset for palliative care patients will be established in cooperation with the Federal Statistical Office in 2011. Potential patient benefit This project has had an enormous impact on the planning and implementation of the national palliative care strategy. This strategy is subdivided into five different domains, reaching from public awareness and services structures to finances, education and research. The results of the project will be used for monitoring future service de- velopment and regional access to palliative care. Based on international data on improvement of patients outcomes through palliative care services whenever cancer or other diseases cannot be cured, we expect to see similar benefit for patients in our country. Dr. Steffen Eychmüller Palliativzentrum Kantonsspital St. Gallen CH-9007 St. Gallen Phone +41 (0)71 494 3551 steffen.eychmueller@kssg.ch Kiss Alexander Physical and psychological predictors of patient fatigue 1 to 10 years after human stem cell transplantation (KLS-02038-02-2007) Chronic fatigue is a common, debilitating consequence among patients who have undergone haematopoietic stem cell transplantation (HSCT) as therapy for malignant diseases of the blood-forming system. Fatigue is a major source of impairment to quality of life (QoL) among these patients, is difficult to treat and is not well understood in terms of aetiology or course. Aims A study was conducted to identify physiological and psychological predictors of fatigue among 104 HSCT recipients, 1-to-10 years post-transplantation. 45 age-andgender-matched healthy individuals served as controls. Methods Cardiovascular, respiratory and activity parameters were recorded using the LifeShirt system during a 24-h dailylife ambulatory assessment. Participants completed an electronic diary (every 50 minutes) on momentary states of exhaustion, energy, mood and situation. Retrospective self-report questionnaires assessed QoL, fatigue, anxiety, depression and HSCT-related complaints. Physical fitness was evaluated by bicycle ergometry. Among patients, the same procedure was repeated one year later. Results In comparison with healthy controls, HSCT survivors were less physically fit and remained impaired on many dimensions of health-related QoL. They also reported significantly higher levels of fatigue, anxiety and depression on the retrospective questionnaires. Electronic diary data partially confirmed these findings, with patients reporting substantially more exhaustion over the day than controls. On physiological measures, patients manifested significantly lower respiratory sinus arrhythmia and higher heart rate (HR) across levels of activity and times of day, indicating impaired cardiac vagal tone; group differences remained significant after adjusting for fitness. On the other hand, groups did not differ in daytime physical or metabolic activity (as indexed by accelerometry and minute ventilation). 179

180 Within the patient group, level of fatigue was strongly associated with anxiety, depression, sleep quality, and pain and dyspnea complaints. However, fatigue was weakly and inconsistently related to physiological or medical risk parameters. Conclusions Cardiac autonomic functioning may be impaired among HSCT survivors, but patterns of daytime activity are similar to healthy controls. HSCT fatigue appears to be related more to extent of perceived symptoms than to concurrent physiological functioning or medical risk indices. The findings suggest that psychological processes related to symptom perception may be importantly involved in the development and maintenance of fatigue. These findings may contribute to understanding and treating fatigue in HSCT survivors. Prof. Dr. Alexander Kiss Abteilung Psychosomatik Universitätsspital Basel Petersgraben 4 CH-4031 Basel Contact: Dr. Paul Grossmann Phone +41 (0)61 265 22 15 grossmanp@uhbs.ch Lehr Hans-Anton Biomedical research on human tissues: In the twilight zone between autonomy and data protection. What do health professionals, patients and lay persons think about issues of consent and transparency in medical research, teaching, and quality control? (OCS 02209-02-2008) Scientific research is of key importance in the development of knowledge on people and their health. This includes not only conducting clinical research on individuals but also research using human tissues. These tissues, taken in the course of treatment, may be used for research. Although this is a common practice, progress in medical science constantly brings up new issues with regard their use. Advances in this field provide new knowledge and possibilities for use of the tissues and the data thus generated, but the advances also raise new ethical problems, such as the possibility to establish a direct link between the human tissue and the personal characteristics of the patient. In view of these developments, it is imperative to understand how the public perceives the use of human tissues for research. The present study, conducted jointly by the University Institute of Pathology (IUP) and the University Institute of Social and Preventive Medicine in Lausanne (IUMSP), seeks to analyze the perceptions and attitudes of different groups in the Swiss population regarding the conservation and use of human tissues for research. This research project includes the following investigations: a systematic review of the literature, an analysis of the legal framework surrounding human tissue research, consultation of experts in the field, a qualitative study of the perceptions and expectations of the general public and health professionals regarding the use of human tissues for research and the development and testing of an instrument for a general population survey. Analysis of the scientific literature indicates that current debate is on the following questions: 1) What information should be given to patients so that they are able to make an informed choice? 2) What kind of consent should be obtained: broad consent or consent to a specific study; explicit or implicit consent? The literature analysis revealed that in some countries, studies have been conducted on perceptions and wishes of the population with regard to consent. It is to be noted that the studies did not investigate public expectations regarding what information should be given. The main results were the following: a) the general public and patients wish to have the opportunity to give or withhold consent to use of their tissues; b) a large majority of persons interviewed would give consent if asked; c) of the different forms of consent possible, general consent is favoured by most. The literature review and the expert interviews allowed us to identify the main issues at stake and to define the themes to be discussed in the focus groups. To facilitate debate, vignettes describing fictitious situations were presented to the participants. The opinions expressed in the focus groups, conducted in the Canton of Vaud, indicate that certain professionals fear that the need to obtain consent from patients to use of their tissues could act as a barrier to research. However, the general public and patients are generally favourable to research. On the other hand, they do express the wish to be explicitly consulted and informed of the possibility of such use, perceived rather as status-enhancing, or, in severe cases, as a means to make sense of one s illness. Patients are ready to consent to use of their tissues for research on the condition that they are considered partners by health professionals. In this context, consent is seen as a means of ensuring that they have been informed rather than as an opportunity to withhold consent. Prof. Dr Hans-Anton Lehr Institut universitaire de pathologie de Lausanne Centre hospitalier universitaire vaudois (CHUV) Rue du Bugnon 25 CH-1011 Lausanne Phone +41 (0)21 314 71 20 Fax +41 (0)21 314 72 05 hans-anton.lehr@chuv.ch Rüesch Peter Information needs of patients with curable adenocarcinoma of the prostate and professionals opinions: An international study (INEPAP) (KLS 02198-02-2008) Objectives Curable cancer of the prostate can be treated by diverse methods of therapy, each of them being defined by specific pros and cons. Therefore, treatment decision is challenging, because patients have to consider a lot of data to understand the practical consequences of different treatment options. However, research indicates that men with prostate cancer are frequently not satisfied with the information offered: Many report not having received sufficient data; others complain about redundant, inapt or little intelligible information. Therefore, it was the purpose

of this study to ameliorate communication between health professionals and patients in the field of prostate cancer. Methods With this purpose in mind, we tried to incorporate both the view of patients and the professionals into the design of one study. Patients answered a questionnaire developed by an international research team and consisting of 92 questions about prostate cancer and its treatment. Additionally, health professionals (urologists, oncologists, general practitioners, nurses, etc.) rated the same questions with regard to their importance for patients. The final sample of the study consisted of 128 patients and 208 professionals from five clinics in the German-speaking part of Switzerland. Results Patients varied greatly with regard to their judgements of prostate cancer topics. Overall, they considered around half of the almost 100 provided topics as essential for appropriate information. However, some patients considered only a few questions as essential, whereas others rated almost all of the topics essential. Moreover, participating patients agreed only moderately on specific topics. This heterogeneity of ratings about what is important to know about prostate cancer is not only a patient phenomenon. On the contrary, even the health professionals varied greatly in judging what might be of significance for patients. Conclusions and suggestions Information needs with regard to treatment decisions of men with curable prostate cancer are broad but very individual, too. It seems hardly possible to reduce information about this disease to a core set of topics that could then be used to print a small booklet. This would still result in a substantial number of men with information needs not sufficiently covered. The results of this study emphasize the function of dialogue between doctor/professional and patient in transferring information on a highly individual level. However, counselling of prostate cancer patients should not be controlled (only) by some standardized guidelines but should overall consider the patients needs.

182 Further, the results suggest that health professionals counsel men with prostate cancer quite variably. This can be confusing for the men concerned. Thus, a good working exchange between doctors and other professionals caring for patients seems to be of particular importance. Case management approaches to the care and coaching of patients with cancer could be helpful to reach this goal. We also think that the use of e-health, respectively Webbased tools, in the field of prostate cancer counselling could offer new ways of individually and flexibly tailored knowledge transfer from professionals to patients. Dr. Peter Rüesch Fachstelle Gesundheitswissenschaften Departement Gesundheit Zürcher Hochschule für Angewandte Wissenschaften (ZHAW) Technikumstrasse 71 Postfach CH-8400 Winterthur Phone +41 (0)58 934 63 09 peter.rueesch@zhaw.ch Schulz Peter J. Cancer and health literacy: Establishing a concept of cancer literacy (OCS 02101-08-2007) Nowadays, the amount of health information for medical laypersons is overwhelming: It is often difficult for them to be adequately informed about issues that are essential to their health. In the case of cancer this complexity is accompanied by many emotions, such as feelings of powerlessness and helplessness or even fear of death, inducing people to avoid being confronted with information on the subject. Consequently, we assume that people lack an adequate understanding of cancer and of aspects of cancer that could be useful for making fundamental decisions regarding their health. The goal of the project was therefore to operationalize and to specify a usable and defined concept of cancer literacy, i. e. to understand what abilities and attitudes make a person cancer literate, what a lay person needs to know in order to be considered literate in cancer prevention, diagnosis and therapy and, eventually, how cancer literate the Ticino population is. Methods and results To operationally define the concept a Delphi study in three consecutive rounds was conducted among a panel of Swiss cancer experts (n=47/48/41 oncologists, GPs, nurses from oncology wards, social workers, public health experts). The result of the Delphi process was a first operational definition of the concept of cancer literacy, i. e. a list of the aspects of cancer that in the experts view laypeople should know to be considered cancer literate. Afterwards, six in-depth interviews with patients with cancer were conducted with the goal to investigate in greater depth their views on the cancer literacy concept as it emerged from the previous step. In particular, we were interested in their perception of experts expectations regarding people s knowledge, attitudes and abilities; their actual knowledge and learning process; perceived deficits in cancer communication; perceived barriers to achieve the ideal knowledge proposed by experts; the expected role of the health system and health care providers. This step yielded a deeper understanding of the value and the limits of the concept of cancer literacy and provided some hints for its refinement. To assess the validity of the resulting concept and to gain first insights into the cancer literacy of the Ticino population, a survey was developed and administered to a sample (n=639) of the general population stratified for gender, age and educational level. The survey highlighted some major deficiencies as regards knowledge about some aspects of cancer. For instance, more than 60 % of the respondents were not aware of the relationship between overweight and cancer. Moreover, the survey revealed some significant knowledge differences between people with different education levels: To mention just one, almost 20 % of women with a lower education level vs. only 2 % of women with a high education level (p > 0.01) had never heard of a Pap test. Practice implications The study helped define the most health illiterate and cancer illiterate segments of the Ticino population and produced information on the best ways to reach these segments in communication campaigns. It also contributed to finding out what aspects of health and cancer literacy are most in need of improvement. This will aid the designing of information campaigns that target the deficiencies. Prof. Dr. Peter J. Schulz Istituto di comunicazione e sanità Università della Svizzera italiana Via Giuseppe Buffi 13 CH-6900 Lugano Phone +41 (0)58 666 47 24 Fax +41 (0)58 666 46 47 peter.schulz@usi.ch Schwappach David Involving chemotherapy patients in the prevention of medical errors a feasibility study (OCS 02109-08-2007) As in all areas of medical care, critical incidents and medical errors can occur in oncology, e. g. when administering drugs. These events can be of considerable harm to patients. In addition to professional activities to improve patient safety, patient involvement in safety has been recommended internationally. An example is the cooperative check of medications. However, this raises the question as to whether patients are able and willing to get involved in safety, and what conditions need to be satisfied. Therefore, the main objective of our study was to investigate whether the involvement of patients in the prevention of errors would be a promising approach. To answer these questions qualitative and quantitative methods were used. First, 60 comprehensive semi-structured interviews with patients undergoing oncological treatment were conducted. In a second step, 4 focus groups (discussion groups) with clinical oncology nursing staff were conducted and content analysis was performed.

Based on these qualitative results, a sample of 470 oncology patients were surveyed using a written questionnaire. In the survey, a behavioural model that had been developed was tested. This model explains under what conditions patients will become involved for their safety in hospital. The results show that many patients are concerned for their safety and errors in their care. A vast majority agrees that they can contribute to the prevention of errors. Patients themselves describe their capabilities as developing in a learning process alongside the treatment course, in which they acquire knowledge and skills concerning what aspects of care to monitor, what to communicate to care providers and how they can engage for their safety. Patients acknowledge the benefit of error monitoring and reporting but perceive the process of notifying staff of potential errors often as unfamiliar and uncomfortable. Behavioural control and subjective norms are the key elements that explain whether patients communicate their perceptions of safety problems. Oncology nurses perceive involvement of patients as their core expertise. They share a general positive attitude towards the approach, even if communication about safety often is a challenge for them. Nurses sensitively apply different strategies to get patients involved through information and motivation. However, they also see room for improvement, particularly in the cultural implementation in hospitals: Patients need to experience from the beginning that it is appreciated that they ask questions or notify us that something is not correct. Based on these results, distinct recommendations can be made to involve patients in the prevention of errors while taking their individual situation into account. To be successful, it is crucial that clinical staff informs, motivates and supports patients. PD Dr. David Schwappach, MPH Stiftung für Patientensicherheit Asylstrasse 77 CH-8032 Zürich Phone +41 (0)43 243 76 70 schwappach@patientensicherheit.ch sired support received either 4 or 16 sessions of brief psychotherapy and were regularly evaluated for a period of a year with regard to their psychological symptoms and quality of life, as this was the case for participating patients who did not wish to have this support. The results showed that for a lot of patients, it is difficult to organize or to accept psychological support; about 20 % of patients included in the study, or 10 % of the total population approached, desired psychological support; patients motivated to receive support were in psychological distress; two-thirds of participating patients showed signs of important emotional detachment with regard to the efficacy of psychotherapeutic support. Data analysis is still ongoing. We conclude 1) that in the oncology setting, psychological support should be proposed proactively, for example through different modes of communication (telephone, e-mail), and more flexibly, for example by consultations at a patient s home; 2) that at least 10 % of patients wish to benefit from psychological support at the beginning of treatment; 3) that patients in psychological distress were also those who desired support and that systematic screening of patients in need of support, for example by means of a questionnaire, may probably not be necessary; and 4) that because of the emotional detachment of patients with cancer, evaluation of the effects of psychotherapies should use other methods than those utilized up to now. This study has produced important results that contribute to the conceptualization and implementation of psychological support in oncology centres and to adjusting scientific investigation of this domain. Prof. Dr Friedrich Stiefel Service de psychiatrie de liaison Centre hospitalier universitaire vaudois (CHUV) Bugnon 44 CH-1011 Lausanne Phone +41 (0)21 314 10 90 Fax +41 (0)021 314 10 86 frederic.stiefel@chuv.ch 183 Stiefel Friedrich Evaluation of individual psychotherapy for emotionally distressed cancer patients: A randomized controlled trial (OCS 01847-02-2006) In order to evaluate the role psychotherapy can play in the oncology setting, in the context of this study psychological support was proposed to every new patient treated between 2006 and 2009 by the Oncology Service of the University Hospital Lausanne (CHUV). Among the 2,000 patients approached, about half of them had been excluded based on the criteria defined in the study, mainly because of organizational reasons (living too far away from the hospital, intensive treatments, etc.), age > 75, advanced disease or language difficulties. A quarter of the patients approached (n=530) refused to participate in the study; of participating patients (n=419), about half of them (n=190) wished to benefit from psychological support, and the other half, who did not desire psychological support, agreed to be regularly evaluated with regard to their psychological state. Patients who de- Stiefel Friedrich Effects of communication skills training on oncology clinicians communication styles and defense mechanisms (KLS 02035-02-2007) The importance of the quality of exchange between patient and physician has been recognised for several decades. Concerning the patient, it has been demonstrated that efficient communication can influence treatment adherence and improve quality of life and satisfaction with regard to care. Concerning the physician, it is known that efficient communication increases job satisfaction and reduces stress and/or burnout. Given the call for patient-centred medicine, all domains of health care are invited to pay attention to communication challenges. This is particularly true of oncology, which implies breaking bad news and because of the social representations of cancer.

184 It is in this context that the Swiss Cancer League organizes Communication Skills Training (CST) with the aim to improve the communication skills of oncology clinicians (physicians and nurses). Conducted in small groups of 8 10 participants and with a total duration of 30 hours, CST starts with a videotaped interview conducted by each participant with a simulated patient and is followed by an analysis of and feedbacks on the videos, role-plays and transmission of communication theory. CST is completed with individual monthly supervision for a period of six weeks and a second videotaped interview with a simulated patient. This study aimed to evaluate the linguistic aspects of CST based on the videotaped interviews; the evaluations consisted of a comparison of the first and the second videotaped interview in CST (pre-/post-comparison) and a comparison with interviews of clinicians who did not participate in CST and who interviewed the same simulated patients with the same scenarios with a six months interval. The group of clinicians having participated in CST consisted of 57 and the control group of 56 oncology physicians and nurses. Communication skills of clinicians were evaluated and measured by means of communication analysis software (LaComm) developed at the Institut Jules Bordet (Brussels, Belgium) by the team under psycho-oncologist Darius Razavi. This software analyzes the logistic content (sentences and words) of interviews and categorizes them by taking into account the three major functions of a consultation: investigation, support and transmission of information. In total, the linguistic content of the interviews is assigned to 44 specific categories; for example, an utterance like Did you start treatment? is categorized as closed binary evaluation, or words like sad or distress are categorized as psychological information. This study demonstrated that clinicians who participated in CST are more inclined than those in the control group to break bad news by using precise words without using medical jargon and that they focus more on psychosocial issues, recognizing the patient as a subject. This study demonstrated a positive impact of CST on the communication skills of oncology clinicians, since the observed changes are in accordance with patient-centred communication. Prof. Dr Friedrich Stiefel Service de psychiatrie de liaison Centre hospitalier universitaire vaudois (CHUV) Bugnon 44 CH-1011 Lausanne Phone +41 (0)21 314 10 90 Fax +41 (0)021 314 10 86 frederic.stiefel@chuv.ch von der Weid Nicolas Long-term outcome of childhood cancer: Incidence and spectrum of late effects (KLS 02215-02-2008) Aim of the study The Swiss Childhood Cancer Survivor Study (SCCSS) is a common project of the Swiss Childhood Cancer Registry and the Swiss Paediatric Oncology Group and is run at the Institute for Social and Preventive Medicine of the University of Bern. Aim of the SCCSS was to know, in general and in many specific aspects, how survivors were doing, what kind of late effects they suffered from, to detect them as early as possible and to treat or alleviate them. Knowledge about long-term toxicities would help to design newer treatment strategies with same efficacy and less morbidity. Methods Included in the SCCSS were all children and adolescents diagnosed with a malignant disease in Switzerland between 1976 and 2003. We looked for current addresses in the former medical files of the patients and through an Internet-based search system. Survivors with established addresses received at their home a comprehensive health questionnaire in the years 2007 2010. Results First results are already available in many domains and have been or will be published soon. Psychological health Psychological troubles are not different in frequency or severity in survivors of paediatric cancer and in the general population. But the proportion of people with severe troubles was higher in the survivors, so that in our opinion, psychological support should be offered to this population. Socio-economic and education status Comparing education level reached in survivors and the general population, no major differences were found. Initially, survivors had more school difficulties, e. g. needed to repeat one school year or received teaching support, but they eventually achieved the same levels of education as the control population. As expected, survivors of brain tumours and patients having had a relapse of their primary cancer (especially leukaemia) showed more problems and often achieved lower education levels. Health behaviours (use of alcohol, tobacco, cannabis) We found different groups of behaviours in the survivors of cancer; compared to the controls, a larger proportion of survivors, especially men, engaged in binge drinking (i. e. consumption of large amounts of alcohol in a short period of time). Survivors were more active than controls in daily physical activities but engaged less in sports, especially women.

Use of the medical/public health system Only a minority (about 20 %) of the survivors of paediatric cancer were involved in a systematic follow-up for their former disease, and the numbers decreased with time. The same was true of the availability of medical files summarizing their former disease and therapy and describing the needed follow-up examinations and schedule. Many survivors found that regular follow-up was unnecessary. Patient benefit This prospective cohort study is very important for both patients and paediatric oncologists. It shows the spectrum of potential late effects and their dynamics and will be able to identify what risk factors are associated with what late toxicities. In the same way, we think that it will be possible also to demonstrate the beneficial effects of more recent therapies, which are much more adapted to the biological behaviour of the disease, sparing unnecessary toxicity in good risk patients ( tailored therapy, individualized oncology). In the last 50 years, paediatric cancer moved from an almost always fatal to a usually curable disease. It is therefore compulsory to early detect, prevent, treat or at least reduce late toxicities in the majority of survivors. Another crucial topic is the transition from paediatric to adult medical care. This point will be the focus of a new study based on the same data and also supported by the Foundation Cancer Research Switzerland and the Swiss Cancer League. PD Dr Nicolas von der Weid Service de pédiatrie Centre hospitalier universitaire vaudois (CHUV) Rue du Bugnon 46 CH-1011 Lausanne Phone +41 (0)21 314 13 34 Fax +41 (0)21 314 33 32 nicolas.von-der-weid@chuv.ch Znoj Hansjörg Posttraumatic personal growth and posttraumatic stress in patients and their partners adapting to cancer (OCS 01741-08-2005) In this longitudinal study, a representative sample of patients with a new primary cancer diagnosis was assessed within eight weeks of diagnosis, six months after diagnosis and 12 months thereafter. Measures included symptoms of emotional distress, psychosocial parameters, pain, aim of medical treatment and the Posttraumatic Growth Inventory (Tedeschi & Calhoun, 1996). In addition, partners were also investigated, because gender and role differences of couples challenged with cancer have been investigated with different results. Aim of the study We intended to describe the longitudinal course of posttraumatic personal growth and posttraumatic stress in the first year post-diagnosis. Second, we intended to identify predictors of perceiving posttraumatic personal growth vs. posttraumatic stress from cancer at the individual and dyadic level for patients and their partners. Method A total of 346 patient names were provided by their doctors. After exclusion based on time since diagnosis and other criteria, 296 of the remaining patients were deemed eligible, 287 consented to receive the assessment by mail, and 218 patients returned a completed questionnaire (74 % response rate). No significant differences were found between responders and non-responders regarding age, stage of disease, ECOG performance status, tumour site, curative versus palliative treatment or partners study participation. During the initial phone call, participating patients were asked whether they had been living with an intimate partner, married or not, for at least six months. If yes and where available, spouses were given full study information on the phone; 166 spouses were deemed eligible and were sent the assessment package together with the patient s and along with full written study information; 137 spouses returned the completed questionnaire (83 % response rate). Measures assessed multiple quality of life (QoL) dimensions including health-related and dyadic QoL as well as symptoms of distress: anxiety, depression, intrusion, avoidance and hyperarousal. The main intention of this study was to understand in more detail how patients and their partners adapt to cancer diagnosis. In order to optimally utilize all gathered data, we decided to analyze t1 and t2 measurements separately and additionally to the longitudinal analysis. Results of the study Multivariate analyses revealed, eight weeks after diagnosis, marked symptoms of distress for 25 % of the respondents. Twelve months after diagnosis 15 % would still need professional help. Most of the patients reported posttraumatic growth (PTG) at least in some respect. PTG appeared together with emotional and cognitive coping, but it was not associated with emotional distress or more progressed disease. These results support the findings that PTG is not a strategy aimed to deny the seriousness of a cancer diagnosis. Moreover, these results indicate that patients reporting PTG realize and accept the bad and the good of a cancer diagnosis. One-third of the variance of PTG is explained by active and target oriented coping, seeking social support and emotion regulation. This result has important clinical significance, in that these strategies can be fostered through psychological interventions. Among couples coping with cancer diagnosis, the effects of gender, role (patient vs. spouse) and patient relationship status (single vs. partnered) on quality of life (QoL) have been investigated with inconsistent results. The present study examined the impact of gender, role and relationship status on male and female patients, their spouses and non-partnered patients. Multivariate analyses of covariance revealed lower QoL for women versus men, and for spouses versus patients on a number of measures (health-related QoL, satisfaction with dyadic coping, anxiety and intrusions). 185

Recommendation Female spouses of patients with cancer are at high risk of deteriorated QoL immediately after diagnosis and require special attention to their psychosocial care needs. Our results show that most patients with a cancer diagnosis cope well. However, partners are often overlooked. Especially female partners, who take on care-taking burden, suffer from detriments in quality of life. Specific psychological help and coaching is not only important for patients but is also especially important for their life partners. 186 Prof. Dr. Hansjörg Znoj Institut für Psychologie Abteilung für klinische Psychologie und Psychotherapie Universität Bern Gesellschaftsstrasse 49 CH-3000 Bern 9 Phone +41 (0)31 631 45 91 Fax +41 (0)31 631 82 12 hansjoerg.znoj@psy.unibe.ch Further completed research project from July 2008 to December 2010 Ansermet François KLS 01705-04-2005 CHF 273,000. Service de psychiatrie de l enfant et de l adolescent (SPEA), Hôpitaux universitaires de Genève (HUG), Genève Biobehavioral responses to stress in adult survivors of a childhood cancer

Psychosocial research List of approved research projects in 2009/2010 Total funds allocated: CHF 1,028,550. De Geest Sabina KFS 02705-08-2010 CHF 112,900. Institut für Pflegewissenschaften, Universität Basel, Basel PROVIVO patient reported outcomes in view of symptom experience of late effects and self-management of adult long-term survivors after allogeneic haematopoietic stem cell transplantation a mixed methods study Despland Jean-Nicolas OCS 02338-02-2009 CHF 251,350. Institut universitaire de psychothérapie (IUP), Département de psychiatrie, Centre hospitalier universitaire vaudois (CHUV), Prilly Communication in cancer care: The relationship between clinician s defense mechanisms, patient satisfaction and information recall 187 Ehlert Ulrike KFS 02662-08-2010 CHF 173 600.- Klinische Psychologie und Psychotherapie, Psychologisches Institut, Universität Zürich, Zürich Psychobiological factors influencing the course of HPV infections in young women: a longitudinal study Kiss Alexander OCS 02400-02-2009 CHF 187,200. Abteilung Psychosomatik, Bereich Medizin, Universitätsspital Basel, Basel A cognitive-behavioural mindfulness intervention to improve health-related quality of life, depression and fatigue among long-term haematopoietic stem cell transplant survivors Mueller Michael D. KFS 02456-08-2009 CHF 116,500. Gynäkologie und gynäkologische Onkologie, Universitätsklinik für Frauenheilkunde, Inselspital, Bern Creating and validating a patient-pertinent instrument to assess symptoms experienced related to surgical wounds in women with vulvar neoplasms a mixed methods study (WOMAN-PRO) Stiefel Friedrich KFS 02353-02-2009 CHF 124 200. Service de psychiatrie de liaison (PLI), Centre hospitalier universitaire vaudois (CHUV), Lausanne Effects of communication skills training on oncology clinicians defense mechanisms, communication outcomes and working alliance extension Tschudin Sibil KLS 02577-02-2010 CHF 62,800. Gynäkologische Sozialmedizin und Psychosomatik, Frauenklinik, Universitätsspital Basel, Basel Fertility preservation in young female cancer patients assessment of needs regarding decision-making and development of a decision-aid

Psychosocial research Presentation of approved research projects in 2009/2010 188 De Geest Sabina PROVIVO patient reported outcomes in view of symptom experience of late effects and self-management of adult long-term survivors after allogeneic haematopoietic stem cell transplantation a mixed methods study (KFS 2705-08-2010) Duration: 01.01.2011 01.07.2013 Long-term survivors after allogeneic haematopoietic stem cell transplantation (HSCT) are presumably at a lifelong increased risk for developing various adverse side effects, also termed late effects. In addition to objective measures, in particular the collection of patient self-report is important for the early detection, management and alleviation of these symptoms. Moreover, health-promoting self-management behaviours might minimize the impact of chronic diseases. This multicentre study (Basel and Zurich) uses a mixedmethod design to develop a self-report instrument assessing symptom experience after HSCT. For the development of the instrument qualitative and quantitative research methods are used, and the content is based on the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) symptom item bank recently developed by the National Cancer Institute (USA). Patient interviews, an expert survey and a review of the literature will be conducted. In a subsequent study phase, the instrument will be validated in a sample of 300 patients ( 1 year after allogeneic HSCT). Additional data will be collected in order to investigate the relationship between symptom experience and objectively measured late effects, the perception of late effects by patients and their self-management (i. e. coping with emotions, roles, and medical and healthrelated tasks). The systematic assessment of patient-reported outcomes can be an effective means of secondary prevention in order to timely detect, diagnose and manage late effects. Prof. Dr. Sabina De Geest Institut für Pflegewissenschaften Universität Basel Bernoullistrasse 28 CH-4056 Basel Phone +41(0)61 267 30 40 Fax +41 (0)61 267 09 55 sabina.degeest@unibas.ch Despland Jean-Nicolas Communication in cancer care: The relationship between clinicians defense mechanisms, patient satisfaction and information recall (OCS 02338-02-2009) Duration: 01.06.2009 01.12.2011 Communication has become a key element in oncology and has important consequences for both patients and clinicians well-being. Clinicians often need to regulate the emotions that occur during the discussion of sensitive topics, such as limited life expectancy, which might influence the quality of communication. Aim We wish to better understand how the clinicians emotional regulation might influence communication in oncology. Method We analyze discussions between patients and their clinicians in several hospitals in the French-speaking part of Switzerland. We pay particular attention to the clinicians defence mechanisms that are used to react to the emotional content of the discussions. Potential advantages for the patients A better understanding of the influence of the clinicians emotional regulation of communication in oncology will allow improvement in patient-clinician communication. Prof. Dr Jean-Nicolas Despland Institut universitaire de psychothérapie (IUP) Département de psychiatrie Centre hospitalier universitaire vaudois (CHUV) Site de Cery Bât. Les Cèdres CH-1008 Prilly Phone +41 (0)21 643 63 85 jean-nicolas.despland@chuv.ch Kiss Alexander A cognitive-behavioural mindfulness intervention to improve health-related quality of life, depression and fatigue among long-term haematopoietic stem cell transplant survivors (OCS 2400-02-2009) Duration: 01.09.2009 01.03.2012 Haematopoietic stem cell transplantation (HSCT) is a valuable treatment employed to cure a variety of malignant blood disorders, bone marrow deficiency diseases and other diseases. Thanks to this therapy, many patients survive disorders that in earlier times were fatal. Nevertheless, there are often long-term adverse and challenging consequences of treatment, which include immunosuppressive conditions, graft-vs.-host disease (GvHD), other disorders related to chemotherapy toxicities, chronic fatigue and sexual dysfunction. Because these conditions can often impair normal physical, professional and recreational activities, and social relationships, many patients

report long-term impairment of sense of well-being, reflected by low levels of health-related quality of life (HRQoL) and high levels of depression and anxiety. Very little effort has been expended in examining whether behavioural interventions can serve to improve distinct parameters of well-being, e. g. HRQoL, depression, fatigue and anxiety. Aim Mindfulness-based intervention (MBI) is a group behavioural program aimed at improving aspects of well-being for patients with a broad spectrum of chronic disorders (detailed description provided later). The primary goal of this investigation is to examine whether MBI is a feasible and effective intervention for HSCT survivors in terms of enhancing different dimensions of HRQoL (e. g. psychological functioning, positive emotions, social contact and ability to enjoy life) and decreasing depression, fatigue and anxiety. Methods Using a controlled patient-preference procedure, MBI is compared to a comparison intervention of augmented optimal medical care, where patients, additional to usual medical care, receive brief telephone medical and psychosocial consultations twice a month during the intervention phase. Feasibility of interventions will be evaluated by measuring aspects of acceptability of interventions (percentage of invited patients who participate, the dropout rate for the program, the average weekly attendance rate and the degree to which patients perceive that their personal goals for the intervention have been met). Efficacy of treatment will be evaluated by validated inventories of HRQoL, depression and fatigue as primary outcomes. Anxiety, personal growth and physical health status will be employed as secondary measures. We plan to include 100 patients in the study and to examine benefits directly after the intervention period and at 3 months follow-up. Results This study is ongoing, and 51 patients are thus far participating. Few patients dropped out of the study before completing the intervention (<10 %), and all dropouts were due to documented serious medical problems. However, other results have not yet been analyzed. Patient benefit This study will be one of the first controlled investigations to evaluate a complementary behavioural intervention for the purpose of enhancing the well-being of HSCT survivors. Finding will indicate whether MBI or telephone consultation augmented care is effective at enhancing quality of life among HSCT survivors. Prof. Dr. Alexander Kiss Abteilung Psychosomatik Universitätsspital Basel Petersgraben 4 CH-4031 Basel Phone +41 (0)61 265 53 09 akiss@uhbs.ch Mueller Michael D. Creating and validating a patientpertinent instrument to assess symptoms experienced related to surgical wounds in women with vulvar neoplasms a mixed methods study (WOMAN-PRO) (KFS 02456-08-2009) Duration: 01.01.2010 01.07.2012 Post-surgery complications in women with vulvar neoplasms (vulvar intraepithelial neoplasia and vulvar cancer) are still high, and an instrument assessing patients selfreported post-vulval surgery symptom experiences is lacking. This study aims to develop and validate a postoperative instrument to assess symptom experiences in women with vulvar neoplasms. In this mixed-method project 20 patients were interviewed, a WOMAN-PRO instrument was developed and content validity was tested by 6 experts and 10 patients. The psychometric properties of the instrument and the prevalence of symptoms will be examined in a cross-sectional study at the university hospitals in Munich, Freiburg i. Br., Berlin, Düsseldorf, Zurich, Basel, and Bern and the Cantonal Hospital St Gallen (n=150). The goal of this project is that symptom assessment becomes a standard component of clinical practice (to promote the early detection and treatment of symptoms) and research. Prof. Dr. Michael D. Mueller Gynäkologie und gynäkologische Onkologie Universitätsklinik für Frauenheilkunde Inselspital Bern Effingerstrasse 102 CH-3010 Bern Phone +41 (0)31 632 12 03 Fax +41 (0)31 632 12 05 michael.mueller@insel.ch Stiefel Friedrich Effects of communication skills training on oncology clinicians defense mechanisms, communication outcomes and working alliance extension (KLS 02715-08-2010, prolongation of the project KLS 02353-02-2009) Duration: 01.05.2009 01.03.2011 For more than ten years, the Swiss Cancer League has organized Communication Skills Training (CST) for physicians and nurses who work with patients with cancer. This training program is based in particular on the analysis of filmed interviews conducted by each participant with a simulated patient (an actor simulating a patient with cancer with a complex situation). Conducted in small groups of 8 10 participants, the training lasts 16 hours. It begins with the filmed interview with a simulated patient, and it is completed by a monthly individual supervision for a period of six months and another day of training with a second filmed interview with a simulated patient. Although research has demonstrated that this type of training enables clinicians to adopt a more patient-centred communication style, the question as to how this training amelio- 189

190 rates communication skills remains unanswered. To better know and understand the mechanism that leads to improvement, the filmed interviews before and after CST were analyzed and compared with filmed interviews of clinicians with simulated patients with a six-month interval who did not participate in CST. The analysis of the interviews was based on methods utilized in psychotherapy, especially the identification of defence mechanisms. Defence mechanisms, such as denial or intellectualization, are unconscious processes triggered by emotions that may emerge during an interview, for example; they aim to protect the individual from threatening affect. Although defence mechanisms protect the clinicians, they also have the effect that the clinician s perception of the patient is coloured by the clinician s psychological state. This hampers the clinician s capacity to adequately perceive the needs of the patient. The results of the study show 1) that during an interview of a quarter of an hour with a simulated patient, clinicians defence mechanisms are triggered 15 times, illustrating the affective load of such interviews, and 2) that defence mechanisms of participants are modified by CST, which increase the proportion of mature defence mechanisms, leading to more appropriate perception of the patient. To conclude, this study demonstrated that patient interviews represent an important stressor for the clinician and that improvement of communication skills by CST is linked to utilization of more mature defence mechanisms. The results have increased our knowledge of processes of improvement of communication skills by CST and call for a modification of teaching with an increased focus on clinicians emotional experiences and their professional identity. Prof. Dr Friedrich Stiefel Service de psychiatrie de liaison Centre hospitalier universitaire vaudois (CHUV) Rue du Bugnon 44 CH-1011 Lausanne Phone +41 (0)21 314 10 90 Fax +41 (0)021 314 10 86 frederic.stiefel@chuv.ch Tschudin Sibil Fertility preservation in young female cancer patients assessment of needs regarding decision-making and development of a decision-aid (KLS 02577-02-2010) Duration: 01.07.2010 01.07.2012 Impaired fertility may be a consequence of successful cancer treatment, and the use of one of the fertility preservation (FP) techniques being developed currently might therefore be an option for all young patients with cancer. Decisions on fertility preservation have to be made in the short time period after diagnosis and before onset of cancer treatment, and the dilemma confronting affected patients, their families and their caretakers is considerable. The aim of this study is to gain deeper insight into the needs and conflicts occurring during this decision-making process. The study addresses former and current female patients with cancer at young age and consists of two parts. Part 1 is an anonymous online survey, which will be available via a link on cancer and fertility websites. Part 2 consists of standardized focus groups facilitated by a psychologist. The knowledge gained through this study will aid development of a standardized instrument that complements and supports shared decision-making in fertility issues and FP for young patients with cancer and their medical caretakers. Dr. Sibil Tschudin Gynäkologische Sozialmedizin und Psychosomatik Frauenklinik Universitätsspital Basel Spitalstrasse 21 CH-4031 Basel Phone +41 (0)61 265 90 43 stschudin@uhbs.ch Further approved research project 2009/2010 Ehlert Ulrike KFS 02662-08-2010 CHF 173 600.- Klinische Psychologie und Psychotherapie, Psychologisches Institut, Universität Zürich, Zürich Psychobiological factors influencing the course of HPV infections in young women: a longitudinal study

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Epidemiological research 193 Epidemiological studies on mobile telephones and cancer Since the introduction and rapid spread of mobile telephones in the 1990s, the question as to whether the radiofrequency electromagnetic fields of cellular phones increase brain tumour risk has become an increasingly important public health concern. The use of mobile phones is so widespread that even a small tumour risk due to exposure to radiofrequency radiation emitted by cellular phones would result in increases in general population incidence rates. The Interphone study is the largest epidemiological study of mobile phone use and brain tumours to date. This case-control study included 13 countries, with coordination by the World Health Organization (WHO). Case-control is a retrospective epidemiological study design where people with a disease (cases) are matched with people who do not have the disease (controls). The studies compare the groups with respect to past exposure to the potential risk factor and look for differences. For example, if it were found that persons with brain tumours used their mobile phones significantly more often than comparable control persons, that would be an indication of increased risk. The overall evaluation of the Interphone study is based on 2,400 cases of meningioma (brain tumours that develop from the meninges), 2,700 cases of glioma (brain tumours arising from glial cells), and 5,600 matched controls with no brain cancer, in people 30 60 years of age [1]. Evaluation of all data revealed a 20 % lower risk of meningioma and glioma for regular mobile phone users compared to non Prof. Martin Röösli, PhD Head of the Unit for Environmental Epidemiology and Risk Assessment, Swiss Tropical and Public Health Institute, Basel Kerstin Hug, MD Responsible for the Documentation and Service Database ELMAR Electromagnetic Radiation and Health, Swiss Tropical and Public Health Institute, Basel

194 regular users. However, in a subset of users the highest users, with a history of at least 1,640 hours of call time the risk of glioma was 40 % higher compared to non regular users. These contradictory findings raise the question of the explanatory power of epidemiological studies. The conclusiveness of environmental epidemiological studies Demonstrating cancer risk due to exposure to environmental factors is particularly difficult because the negative effects may occur only after a long period of exposure. To determine how a potentially harmful substance affects the organism and what biological processes are involved, experimental studies with cells or animals are helpful. However, the extent to which the findings can be applied to human beings is always uncertain, so that in the end only longitudinal studies with people can provide definitive answers. The WHO also attaches the most importance to these epidemiological studies [2]. Studies with human participants present a number of practical difficulties. The type of study least prone to error would be a very large randomised trial in which half of the participants were randomly assigned to mobile phone exposure for 10 years and the other half were not. Naturally, studying cancer risk in that way is not feasible for ethical and practical reasons, so we must rely on the findings of observational epidemiological studies. The three biggest difficulties with these studies are presented in the following taking the example of studies on mobile phone use. 1. The influence of confounders In observational study designs, cancer incidence is compared in dependency upon mobile phone use. Here there is always the question as to how comparable the participants with high mobile telephone use are with the participants with no or infrequent phone use. If there is a difference in cancer rates between cellular phone users and non-users, the reason is not necessarily mobile phone radiation. The two groups may differ in other characteristics or behaviours that affect cancer risk. These confounders can distort the results of a study. This problem became particularly evident in a large Danish cohort study [3]. In cohort studies it is examined whether a group of persons who are exposed to a potential risk factor have a higher incidence of disease than persons in a control group that is not exposed or less exposed to this factor. In the study in Denmark, as compared to the rest of the population long-term mobile phone users were found to have a lower risk of brain tumours. At the same time, among men, long-term cellular phone users were also found to have a lower risk of lung cancer. Among women, long-term mobile phone users had a higher risk of uterine cancer. As it is very unlikely that cellular phone radiation affects lung cancer risk or uterine cancer risk, this indicated that other lifestyle factors could have led to the results. A plausible explanation, for example, is that men who started using mobile phones shortly after they were first introduced may have had higher incomes and may have smoked less. 2. Distortion of results due to selection bias In principle, lifestyle factors that also affect cancer risk, such as smoking or alcohol consumption, could be captured and taken into consideration in the analysis. In the Danish study, however, no such information was available because the study was based on

data from cancer registries. In the Interphone study, great efforts were undertaken to capture all possible confounders by personally surveying all study participants. Due to the effort required, willingness to participate in such a study can depend on the state of health of the participants as well as their mobile phone use, and it is generally not very high, especially among healthy participants. Already at the start a low rate of participation in one of the groups can result in systematic differences between the groups to be compared and thus lead to a distortion of the study results. There are indications that this is what happened in the Interphone study: Since willingness to take part in the study was particularly low in healthy control persons who did not use cellular phones, mobile phone users came to be overrepresented in the control group. Through this, the cellular phone use of healthy persons compared to persons with brain tumours was overestimated, and the statistical analyses yielded a seemingly reduced risk of cancer with regular mobile phone use. 3. Estimating exposure The third big difficulty with observational studies in epidemiology is estimating and classifying exposure correctly. Retrospective studies like the Interphone study must frequently rely on participants self-reports, as no objective exposure data for the past, for instance from network providers, are available. Since people do not recall the exact number and duration of phone calls years or decades ago, their self-reports are fraught with great uncertainties. If patients and healthy participants make on average the same errors in their exposure estimates and if there is a correlation between the exposure estimates and actual call time, the effect on the results is not dramatic. The resulting erroneous classification of the participants leads to an underestimate of the association, if there is a connection between exposure and disease. And if there is no connection, the study will not erroneously compute an association. However, it is problematic if self-reports differ between patients and control persons. It is known that persons with a disease tend to overestimate their past exposure to environmental risk factors, because they are looking for reasons why they became ill. In contrast, persons without a disease tend to underestimate their exposure. As a result of this constellation, study results can mistakenly indicate an association between exposure and disease that in reality does not exist. Whether or not this phenomenon is the reason for the increased risk of glioma among mobile phone users with the highest exposure levels in the Interphone study cannot be determined conclusively and is a matter of controversy in expert circles. Brain tumours caused by mobile phones? Epidemiological studies are needed to clarify the long-term risks of exposure to potential environmental factors such as electromagnetic fields. However, due to their non-experimental design the studies are prone to errors. For this reason it is necessary to investigate a question using different types of studies in different contexts. The complementary information provided by the different studies yields an overall picture that allows us to assess the scientific evidence. As mentioned, the Interphone study and other similar, previously conducted studies did not conclusively determine whether mobile phone use increases brain tumour risk. If it did, the widespread and nearly global use of mobile communications would lead us to expect an increase in brain tumour incidence. However, higher incidence rates have not been found 195

196 based on evaluations of cancer registry data in Scandinavia [4], England [5], or the United States [6]. Although these data tend to speak against an association, it should be noted that long-term risk that would become manifest after more than 20 years of exposure is not yet discernible in the current incidence rates. In summary, the evidence to date does not indicate that cellular phone use causes an increase in brain tumour risk. But there are still only few studies on mobile phone use longer than 15 years and on the effects of cellular phone use on children and adolescents. Prof. Martin Röösli, PhD Martin Röösli is an environmental epidemiologist with a background in atmospheric science. He is head of the Unit for Environmental Epidemiology and Risk Assessment at the Swiss Tropical and Public Health Institute. His research deals with the effects of environmental factors on health, such as electromagnetic fields, air pollution, noise, ionizing and non-ionizing radiation, and passive smoking. Phone +41 (0)61 284 33 88, martin.roosli@unibas.ch www.swisstph.ch References 1. Interphone Study Group. Brain tumour risk in relation to mobile telephone use: results of the Interphone international case-control study. Int J Epidemiol. 2010 Jun;39(3):675-94. 2. International Agency for Research on Cancer (IARC). IARC monographs on the evaluation of carcinogenic risks to humans. Non-Ionizing radiation, part 1: static and extremely low-frequency (ELF) electric and magnetic fields, volume 80. Geneva: World Health Organization and IARC Press; 2002. 3. Schüz J, Jacobsen R, Olsen JH, Boice JD Jr, McLaughlin JK, Johansen C. Cellular telephone use and cancer risk: update of a nationwide Danish cohort. J Natl Cancer Inst. 2006 Dec 6;98(23):1707-13. 4. Deltour I, Johansen C, Auvinen A, Feychting M, Klaeboe L, Schüz J. Time trends in brain tumor incidence rates in Denmark, Finland, Norway, and Sweden, 1974-2003. J Natl Cancer Inst. 2009 Dec 16;101(24):1721-4. 5. de Vocht F, Burstyn I, Cherrie JW. Time trends (1998 2007) in brain cancer incidence rates in relation to mobile phone use in England. Bioelectromagnetics. 2011 Jul;32(5):334-9. doi: 10.1002/bem.20648. Epub 2011 Jan 28. 6. Inskip PD, Hoover RN, Devesa SS. Brain cancer incidence trends in relation to cellular telephone use in the United States. Neuro Oncol. 2010 Nov;12(11):1147-51. Kerstin Hug, MD Kerstin Hug is a research assistant at the Swiss Tropical and Public Health Institute and is responsible for the ELMAR Documentation Service and Database on electromagnetic radiation and health. In her work she focuses on systematic literature research, methodological evaluation of epidemiological studies, and writing reviews of the literature on non-ionizing radiation. Phone +41 (0)61 284 83 66 kerstin.hug@unibas.ch www.elmar.unibas.ch

The importance of cancer registries for health policy 197 Cancer is a significant disease in Switzerland: Four out of ten people are diagnosed with cancer at some point in their lives, and 16,000 people die of cancer each year. The number of cases of cancer in Switzerland is expected to increase in the future due to the ageing population. Switzerland must have reliable data to monitor the development of cancer, to better understand the causes of cancer, and to assess the effectiveness and quality of prevention and treatment. These data are systematically collected by cantonal cancer registries and then aggregated and analyzed on a national level by the National Institute for Cancer Epidemiology and Registration (NICER). In February 2011 NICER, the Swiss Childhood Cancer Registry (SCCR), and the Federal Statistical Office (FSO) published the report Cancer in Switzerland: Situation and development from 1983 to 2007. This report provides an overview of the national cancer incidence and many other aspects of cancer, and it is an important, evidence-based foundation for decision-making in politics, prevention, and medical practice. At present there are 16 cantonal or regional cancer registries, which cover only about twothirds of the population of Switzerland. Therefore, for estimates for the whole of Switzerland these figures have to be extrapolated. Since it is assumed that there are differences in cancer incidence among the different language regions of Switzerland, certain distortions of the data are possible. These statistical problems will be solved only once there is fullcoverage data collection in all cantons. NICER and the cancer registries therefore support the continued efforts of the Federal Council to create a basis in federal law for full-coverage, nationally coordinated cancer registration in Switzerland. National Institute for Cancer Epidemiology and Registration (NICER) c/o ISPMZ University of Zurich Seilergraben 49 CH-8001 Zurich Phone +41 (0)44 634 53 74 info@nicer.org www.nicer.org

Epidemiological research List of completed research projects from July 2008 to December 2010 Bouchardy Christine KLS 01759-08-2005 CHF 310 600. Registre genevois des tumeurs, Institut national pour l épidémiologie et l enregistrement du cancer (NICER), Genève Epidemiologic research on the impact of genetic factors in breast cancer occurrence among the female population of Geneva: A study from the first Familial breast cancer registry in Switzerland 198 Ess Silvia KLS 01766-08-2005 CHF 259 500. Krebsregister St. Gallen-Appenzell, Kantonsspital St. Gallen, St. Gallen Patterns of care and survival in breast cancer patients in Switzerland Levi Fabio OCS 01633-02-2005 CHF 265 620. Unité d épidémiologie du cancer et Registres vaudois et neuchâtelois des tumeurs, Institut universitaire de médecine sociale et préventive, Centre hospitalier universitaire vaudois (CHUV), Lausanne An integrated network of case-control studies on cancer: Nutrition, other environmental and genetic factors Zwahlen Marcel OCS 01869-02-2006 CHF 171 400. Institut für Sozial- und Präventivmedizin, Universität Bern, Bern Risk of childhood leukemia varies little by familial socio-economic status while survival time after a brain tumor diagnosis varied considerably by familial socio-economic status Epidemiological research Presentation of completed research projects from July 2008 to December 2010 Bouchardy Christine Epidemiologic research on the impact of genetic factors in breast cancer occurrence among the female population of Geneva: A study from the first Familial breast cancer registry in Switzerland (KFS 01759-08-2005) Breast cancer is a public health priority in Switzerland. Family history is one of the major risk factors for breast cancer. To perform innovative studies on the effect of hereditary factors on breast cancer occurrence and outcome, we set up the first and unique Familial breast cancer registry in Switzerland, which currently contains validated family histories of cancer for more than 6,000 patients. Objectives of the study The objectives of our study are to compare pathological characteristics of cancers occurring in the same family and to evaluate the concordance of prognosis between firstdegree relatives with breast cancer. Potential patient benefit These studies will allow to a better understanding of the genetic factors influencing disease prognosis and make it possible in the near future to improve surveillance and care of women with high risk breast cancer. Prof. Dr Christine Bouchardy Registre genevois des tumeurs Institut de médecine sociale et préventive Département de médecine et santé communautaire Université de Genève Bd de la Cluse 55 CH-1205 Genève Phone +41 (0)22 379 49 50 christine.bouchardymagnin@unige.ch Methods We will compare tumour characteristics between women with breast cancer belonging to the same family, and investigate whether the mother or sister s prognosis influences the patient s prognosis.

Ess Silvia Patterns of care and survival in breast cancer patients in Switzerland (KLS 01766-08-2005) Background Breast cancer is the most common malignancy and the first cause of premature mortality for women in Switzerland. Two recently published studies described geographical disparities in breast cancer mortality and 5-year relative survival rates after controlling for prognostic factors like tumour size and nodal status, suggesting that other factors than stage at diagnosis might influence outcome. Although in other countries treatment of breast cancer in specialized units has been shown to result in better outcomes, there is still much debate as to whether specialization in breast cancer care is needed in Switzerland and whether differences that matter to the patient exist. Aims and Methods The aims of this study were to analyze whether differences in the implementation of state-of-the-art management exist and to find predictors for adequate and poor management of early breast cancer in Switzerland. We included 4,800 patients newly diagnosed with breast cancer in the years 2003 2005. Patients were selected from seven population-based cancer registries (Basel, Geneva, Grisons-Glaris, St Gallen/Appenzell, Ticino, Valais and Zurich). Based on the requirements of the European Society of Mastology (EUSOMA) Audit system on Quality of Breast Cancer Treatment criteria, a database was designed. Items included detailed information on patient and tumour characteristics, diagnosis circumstances and treatments planned and delivered as part of the first therapeutic concept. A 10-item score of state-of-the-art management was defined based on national and international guideline items. The score included five items for surgical management, one item for histopathology reporting and four items for adjuvant radiotherapy and systemic treatment. Results Two-thirds of patients were treated with a breast conserving surgery. Age, bigger tumours and residence in a rural area increased the probability to have a mastectomy. We observed geographical disparities regarding the utilization of new surgical procedures (sentinel node biopsy, skin sparing mastectomy) and pre-treatment diagnosis. On the other hand, few differences existed regarding adjuvant radiotherapy and systemic therapies. In one-third of the patients, management met guidelines in all items, whereas in about one-fifth, three or more items did not comply. Treatment by a surgeon with a caseload in the upper tercile and team involved in clinical research were independent predictors of a high score, whereas treatment by a surgeon with a caseload in the lower tercile was associated with a low score. Socioeconomic characteristics such as income and education were not independent predictors, but patient s place of residence and age independently predicted management according to recommendations. Potential patient benefit In the past few years, increasing awareness of variations in the quality of health care across geographic areas as well as providers in other countries has helped to propel a quality improvement movement. In the Swiss health system, characterized by freedom of choice of provider, the importance of an informed choice of referring physicians and patients is paramount. The introduction of accredited breast units in the near future will increase transparency, facilitate this informed choice and contribute towards reducing disparities. Dr. Silvia Ess Krebsregister St. Gallen-Appenzell Kantonsspital St. Gallen Flurhofstrasse 7 CH-9000 St. Gallen Phone +41 (0)71 494 21 17 Fax +41 (0)71 494 61 76 silvia.ess@kssg.ch Levi Fabio An integrated network of case-control studies on cancer: Nutrition, other environmental and genetic factors (OCS 01633-02-2005) This is an integrated epidemiology research scheme, designed to identify and better quantify environmental and genetic risk factors for several common cancers including head and neck (HNC), breast and colorectal cancers and to estimate the relative and attributable risk in the Swiss and other Southern European populations. The program originated in the late 1980s and has contributed to the definition and quantification of environmental (tobacco, alcohol, diet, physical exercise, etc.) and familial factors in cancer risk. This project has been included in international meta analyses and pooled analyses of various neoplasms including head and neck, breast and colon. Epidemiological data are collected through interviews of patients with cancer and controls admitted to the CHUV in Lausanne. At the end of 2010, the overall dataset included about: 950 cases of HNC cancers (of oral cavity and pharynx, oesophagus and larynx), 600 of colorectal cancers, 800 of breast cancers, and over 4,500 controls. Our recent findings indicated that citrus fruit has a protective role against cancers of the digestive and upper respiratory tract. No association was found with breast cancer. We were involved in the International Head and Neck Cancer Epidemiology (INHANCE) consortium, which includes data from 33 HNC studies worldwide, and a total of about 25,000 cases of 33,000 controls. The influence of family history on HNC risk was investigated, showing an increased risk (odds ratio, OR=1.7) in first-degree relatives that was higher when the affected relative was a sibling rather than a parent and for more distal HNC anatomic sites (hypopharynx and larynx). The risk was also higher in those exposed to tobacco. The OR rose to 7.2 among subjects with family history who were alcohol and tobacco users. 199

200 Findings of the INHANCE study also suggested that the risks of HNC for beer and liquor are comparable. A greater than multiplicative effect between ever tobacco and alcohol use was observed for HNC risk. The population attributable risk for tobacco or alcohol was 72 % for HNC, of which 4 % was due to alcohol alone, 33 % was due to tobacco alone and 35 % was due to tobacco and alcohol combined. Quitting tobacco smoking resulted in a HNC risk reduction in the short term. For alcohol use, a beneficial effect on the risk of HNC was only observed after 20 years of quitting. Additional and more detailed collaborative analyses within the INHANCE consortium were conducted on: a) total exposure and exposure rate effects of alcohol and smoking and risk of HNC; b) cessation of alcohol drinking, tobacco smoking and the reversal of HNC; and c) interaction between tobacco and alcohol use and risk of HNC. The major results of the research are published to increase the project impact on various aspects of public health and prevention and, in particular, the assessment of the individual risks and their public health implications. Prof. Dr Fabio Levi Unité d épidémiologie du cancer et Registres vaudois et neuchâtelois des tumeurs Institut universitaire de médecine sociale et préventive Centre hospitalier universitaire vaudois (CHUV) Chemin des Falaises 1 CH-1011 Lausanne Phone +41 (0)21 314 73 11 fabio.levi@chuv.ch When analyzing survival after a cancer diagnosis, SES differentials were virtually absent for leukaemia patients but existed for other childhood cancers, especially for patients with a tumour of the central nervous system. Mortality was lower in higher SES groups compared to lower SES groups. Depending on the SES measure used, hazard ratios ranged from 0.48 (95 % CI: 0.28 0.81) to 0.71 (95 % CI: 0.44 1.15) when comparing the highest with the lowest SES group. This might imply an association of SES with access to health care and treatment decisions, which in turn would be associated with treatment outcome. To improve health conditions and care in all socioeconomic groups in high-income countries with mandatory health insurance like Switzerland, it is important to understand the causes of childhood cancer and the mechanisms that are responsible for differences in survival after a cancer diagnosis in children. Prof. Dr. Marcel Zwahlen Institut für Sozial- und Präventivmedizin Universität Bern Finkenhubelweg 11 CH-3000 Bern Phone +41 (0)31 631 35 11 zwahlen@ispm.unibe.ch Zwahlen Marcel Risk of childhood leukemia varies little by familial socio-economic status while survival time after a brain tumor diagnosis varied considerably by familial socio-economic status (OCS 1869-02-2006) Research on origins and determinants of childhood cancer is still important, because the aetiology of childhood cancer remains poorly understood. Whether diseases are occurring more frequently in persons with lower socioeconomic status (SES) is a question that is regularly asked. In a nationwide study of the SCCR and the Swiss National Cohort (SNC) using data of the 1990 and 2000 census, we examined, first, the association of SES level and the risk of leukaemia and, second, the association of SES level and mortality in childhood cancer patients. In the case-control study part we found weak evidence for a positive association of childhood leukaemia with higher education of mother but no evidence of an association with other family indicators of SES. The odds ratio for leukaemia and SES, comparing the highest SES category with the lowest SES category, was 1.37 (1.00 1.89) for mother s education, 0.95 (95 % CI: 0.71 1.26) for father s education and 0.96 (95 % CI: 0.74 1.25) for number of rooms per person. This might imply that childhood leukaemia risk is positively associated with a specific exposure linked to higher education of the mother.

Epidemiological research List of approved research projects in 2009/2010 Total funds allocated: CHF 2,134,950. Bordoni Andrea KFS 02668-08-2010 CHF 232,700. Registro cantonale dei tumori, Istituto cantonale di patologia (ICP), Locarno Indicators of quality of cancer care in Southern Switzerland Bouchardy Christine KFS 02544-02-2010 CHF 315,900. Registre genevois des tumeurs, Institut national pour l épidémiologie et l enregistrement du cancer (NICER), Genève Impact of genetic factors in breast cancer occurrence, treatment and outcome using population-based data from the first Familial breast cancer registry in Switzerland 201 Clough-Gorr Kerri KFS 02553-02-2010 CHF 381,300. NICER, c/o Institut für Sozial- und Präventivmedizin, Universität Zürich, Zürich The Swiss National Cohort (SNC) and the National Institute for Cancer Epidemiology and Registration (NICER) cancer epidemiology study, 1990 2008 Keiser Olivia KFS 02478-08-2009 CHF 225,700. Institut für Sozial- und Präventivmedizin, Universität Bern, Bern Changes and determinants of cancer patterns among persons infected with HIV in the era of combined antiretroviral therapy in Switzerland Levi Fabio KFS 02437-08-2009 CHF 270,000. Unité d épidémiologie du cancer et Registres vaudois et neuchâtelois des tumeurs, Institut universitaire de médecine sociale et préventive, Centre hospitalier universitaire vaudois (CHUV), Lausanne Modelling, interpretation and forecasting of cancer mortality in Europe Michel Gisela KLS 02631-08-2010 CHF 283,300. Institut für Sozial- und Präventivmedizin, Universität Bern, Bern Effectiveness of transition to adult care after childhood cancer Mullis Primus-Eugen KLS 02586-02-2010 CHF 184,300. Abteilung pädiatrische Endokrinologie, Diabetologie und Stoffwechsel, Universitätsklinik für Kinderheilkunde, Inselspital, Bern Risk of cancer and long-term mortality in children treated with growth hormone: Swiss participation in the EU FP7 project Safety and Appropriateness of Growth Hormone Treatment in Europe (SAGhE) Thürlimann Beat KFS 02474-08-2009 CHF 25,900. Brustzentrum, Kantonsspital St. Gallen, St. Gallen Management of breast cancer in the elderly in Switzerland Vounatsou Penelope KLS 02393-02-2009 CHF 215,850. Biostatistics and Computational Sciences Unit, Departement für Epidemiologie und Gesundheitswesen, Schweizerisches Tropen- und Public Health-Institut, Basel Spatio-temporal patterns and forecasting of gender specific lung and other tobacco-related cancer mortality and morbidity rates in Switzerland

Epidemiological research Presentation of approved research projects in 2009/2010 202 Bordoni Andrea Indicators of quality of cancer care in Southern Switzerland (KFS 02668-08-2010) Duration: 01.01.2011 01.01.2014 Study design A prospective descriptive population-based study conducted in a three-year time period at Ticino Cancer Registry. Aims To identify a panel of specific quality of cancer care (QoCC) indicators concerning three cancers (colorectal, prostate, ovary/uterus), so as to assess the quality of the diagnostic and therapeutic process offered in Canton Ticino; to promote a culture of QoCC among health care providers; and to obtain improved patient outcomes in the long term. Methods Specific project research boards will be formed for each type of tumour and the indicators identified will refer to all incident cases occurring from 2011 2013 in Canton Ticino. Potential patient benefit All incident patients resident in Canton Ticino according to the inhabitants control database and diagnosed from 2011 2013, regardless of age, will be included. We expect to collect information for 220, 240 and 70 patients per year with colorectal, prostate and ovarian/uterine cancers, respectively (for a total number of 1,590 cases for the 3-year study period). Dr. Andrea Bordoni Registro cantonale dei tumori Istituto cantonale di patologia (ICP) Via in Selva 24 CH-6601 Locarno Phone +41 (0)91 816 08 23 Fax +41 (0)91 816 08 29 andrea.bordoni@ti.ch Bouchardy Christine Impact of genetic factors in breast cancer occurrence, treatment and outcome using population-based data from the first Familial breast cancer registry in Switzerland (KFS 02544-02-2010) Duration: 01.08.2010 01.08.2012 Breast cancer is a public health priority in Switzerland. Family history is one of the major risk factors for breast cancer. To perform innovative studies on the effect of hereditary factors on breast cancer occurrence and outcome, we set up the first and unique Familial breast cancer registry in Switzerland, which currently contains validated family histories of cancer for more than 6,000 patients. Objectives of the study The objectives of our study are to compare pathological characteristics of cancers occurring in the same family and to evaluate the concordance of prognosis between firstdegree relatives with breast cancer. Methods We will compare tumour characteristics between women with breast cancer belonging to the same family, and investigate whether the mother or sister s prognosis influences the patient s prognosis. Potential patient benefit These studies will allow to a better understanding of the genetic factors influencing disease prognosis and make it possible in the near future to improve surveillance and care of women with high risk breast cancer. Prof. Dr Christine Bouchardy Registre genevois des tumeurs Institut de médecine sociale et préventive Département de médecine et santé communautaire Université de Genève Bd de la Cluse 55 CH-1205 Genève Phone +41 (0)22 379 49 50 christine.bouchardymagnin@unige.ch Clough-Gorr Kerri The Swiss National Cohort (SNC) and the National Institute for Cancer Epidemiology and Registration (NICER) Cancer Epidemiology Study, 1990 2008 (KFS 02553-02-2010) Duration: 01.10.2010 01.10.2013 Objective To answer critical questions related to the burden of cancer in Switzerland. Methods The study population includes the census-based population of Swiss adults ( age 20) living in NICER cancer registry areas (Appenzell, Basel, Geneva, Glarus, Graubünden, Neuchâtel, St Gallen, Ticino, Valais, Vaud, Zurich). Participants are followed forward in time 1990 2008 with up to 18 years of follow-up for cancer outcomes. Information will be collected on incidence, survival, prevalence of cancer, and socio-demographic, lifestyle and geo-cultural characteristics. Aims: 1) Examine gender-specific trends in cancer outcomes. 2) Evaluate gender-specific socio-demographic factors associated with cancer outcomes. 3) Identify gender-specific lifestyle factors associated with cancer outcomes. 4) Create a multi-institution multidisciplinary research board to promote cancer epidemiology research based on the SNC-NICER study platform.

Impact This work will serve as the foundation for the formulation of future prevention strategies, healthcare initiatives and research agendas based on epidemiological data designed to focus on the risk of cancer. Dr. Kerri Clough-Gorr NICER c/o Institut für Sozial- und Präventivmedizin Universität Zürich Seilergraben 49 Phone +41 (0)44 634 53 74 kerri.clough-gorr@nicer.org Keiser Olivia Changes and determinants of cancer patterns among persons infected with HIV in the era of combined antiretroviral therapy in Switzerland (KFS 02478-08-2009) Duration: 01.01.2010 01.01.2012 With the introduction of the highly active antiretroviral therapy in 1996, life expectancy among persons with HIV (PHIV) increased substantially, and AIDS defining conditions decreased. However, improving survival also means that PHIV are living long enough to develop cancers that accompany ageing or are associated with a prolonged immunodeficiency. The aim of the project is to understand relations between immunodeficiency, ageing and the frequency of cancers. This is a collaboration study between the cantonal cancer registries, the Swiss HIV Cohort Study (SHCS) and the International Agency for Research on Cancer (IARC) in Lyon, France. Methods The anonymous linkage between the patient data of the cancer registries and the SHCS allows us to gain an understanding of the reasons for the higher cancer incidence in PHIV. Cancer incidence in PHIV is compared to incidence in the general Swiss population.

204 Patient benefit Knowledge about specific risk factors allows earlier diagnosis and treatment of cancer. Dr. Olivia Keiser Institut für Sozial- und Präventivmedizin Universität Bern Finkenhubelweg 11 CH-3012 Bern Phone +41 (0)31 631 35 15 okeiser@ispm.unibe.ch Levi Fabio Modelling, interpretation and forecasting of cancer mortality in Europe (KFS 02347-08-2009) Duration 01.10.2009 01.10.2012 The main objective of this project, which started in 1993, is to maintain and improve the integrated system for analyzing, modelling and interpreting mortality statistics in Europe created by our international collaborative group from the WHO raw mortality database. Over the last two decades, total cancer mortality trends were favourable, although to a variable degree, in all major European countries, including Switzerland. The major determinants of these favourable trends were the decline of lung and other tobacco-related cancers in men, together with the persistent falls in gastric cancer and the recent appreciable falls in colorectal cancer. In women, relevant contributions came from the persistent decline in cervical cancer and the recent falls in breast cancer mortality, particularly in Northern and Western Europe. Detailed analyses were conducted and published on trends for oral and pharyngeal, stomach, biliary tract, testis, Hodgkin s lymphoma and childhood cancer. There is ample need to monitor cancer mortality in Europe continuously, and the wide diffusion of these statistics can have a substantial impact on prevention and public health. Prof. Dr Fabio Levi Unité d épidémiologie du cancer et Registres vaudois et neuchâtelois des tumeurs Institut universitaire de médecine sociale et préventive Centre hospitalier universitaire vaudois (CHUV) Chemin des Falaises 1 CH-1011 Lausanne Phone +41 (0)21 314 73 11 fabio.levi@chuv.ch Michel Gisela Effectiveness of transition to adult care after childhood cancer (KLS 02631-08-2010) Duration: 01.04.2011 01.04.2014 Despite improving cure rates, two-thirds of childhood cancer survivors experience late effects. Follow-up is thus very important. Whereas follow-up is usually well-organized in paediatric care, transition to adult care has often been lacking in Switzerland. We will study clinic documents and medical records to describe the organization of follow-up for childhood cancer survivors in paediatric care, transition to adult care and the information provided to future carers, parents and patients. Together with information from two questionnaire surveys, organization of follow-up and transition to adult care will be described. This study will help to develop well-organized transition from paediatric to adult care such that long-term followup for childhood cancer survivors can be improved. Dr. Gisela Michel Institut für Sozial- und Präventivmedizin Universität Bern Finkenhubelweg 11 CH-3012 Bern Phone +41 (0)31 631 33 47 michel@ispm.unibe.ch Mullis Primus-Eugen Risk of cancer and long-term mortality in children treated with growth hormone: Swiss participation in the EU FP7 project Safety and Appropriateness of Growth Hormone Treatment in Europe (SAGhE) (KLS 02586-02-2010) Duration: 01.07.2010 01.01.2013 Growth hormone (GH) is crucial for height gain. Diseases associated with lack of GH can be treated by GH replacement. For example, this GH replacement therapy can be applied to children that cannot produce their own GH after radiotherapy. Data on the long-term safety of this therapy are lacking. A European study, in which Switzerland is also contributing, will now investigate these open questions. This study aims to identify the long-term impact of GH therapy on adult height, quality of life, cancer incidence and mortality. Medical data will be collected from patient files in the hospitals. Information about quality of life and current health status will be assessed by questionnaires sent to the patients. Insights in cancer incidence and mortality can be obtained by comparing these data with the mortality statistics of the Swiss Federal Statistical Office and the national cancer data bases. The patients may benefit through an optimization of therapy guidelines based on the findings of this study. Prof. Dr. Primus-Eugen Mullis Abteilung pädiatrische Endokrinologie, Diabetologie und Stoffwechsel Universitätsklinik für Kinderheilkunde Inselspital CH-3010 Bern Phone +41 (0)31 632 9552 primus.mullis@insel.ch

Thürlimann Beat Management of breast cancer in the elderly in Switzerland (KFS 02474-08-2009) Duration: 01.03.2010 01.11.201 About 40 % of all breast cancer cases are diagnosed in patients aged 65 or older. Data on the aging population demonstrate an unprecedented expansion of the segment of the population aged 65 years in the last 20 years. There is an urgent need to understand the factors influencing diagnosis and treatment of breast cancer in the elderly. The aim of this study is to examine the patterns of breast cancer care in elderly patients and to determine predictors for substandard treatment. Methods We will include a subgroup of 2,049 breast cancer patients 65 years of age from the Swiss Breast Cancer Patterns-of-Care study. Three age subgroups will be studied: the young old (65 74 years), the older old (75 84 years) and the oldest old (85 years and older). Patient, tumour characteristics and treatment adherence with national and international guidelines will be analyzed for each of the age subgroups. Predictors for guideline adherence will be analyzed using multivariate regression analysis, adjusting for known risk factors, type of treatment (surgery, radiotherapy, systemic treatment) and age. The potential impact of non-adherence to guidelines will be studied with appropriate statistical techniques. Potential patient benefit This study is unique in providing very detailed data on the quality of breast cancer care in the elderly. Knowledge about the patterns of breast cancer care in the elderly will be crucial to improving diagnosis and treatment in this growing segment of patients. : Prof. Dr. Beat Thürlimann Brustzentrum Kantonsspital St. Gallen 9007 St. Gallen Phone +41 (0)71 494 10 83 Fax +41 (0)71 494 63 68 beat.thuerlimann@kssg.ch Objectives and goals The main objectives of this research are to: 1) produce smooth maps of gender, age and site-specific patterns of tobacco-related cancer mortality since 1969; 2) produce smooth maps of gender, age and site-specific patterns of lung cancer mortality over time adjusted for non-smoking risk factors to obtain an indirect indicator of space-time patterns of smoking hazards; 3) explore differences in cancer mortality rates between linguistic regions, urbanisation and affluence; and 4) develop models for predictions of tobacco-related cancer mortality by region and gender for 2009 2018 and other models. Methods of investigation We propose to accomplish these objectives by employing and further developing Bayesian Poisson and negative binomial: a) spatio-temporal models for area mortality and incidence data; b) shared component models for a joint spatio-temporal analysis of the tobacco-related cancers; c) age-period-cohort models with spatial and temporal random effects to forecast geographical patterns and trends of mortality and incidence; and d) back-calculation models to estimate incidence from mortality data. Significance This research will contribute smooth maps of gender, age and site-specific patterns of lung and other tobacco-related cancer mortality and morbidity over time. The maps will identify discrepancies in disease burden and assist implementation and evaluation of the National Program Tobacco. This information will be useful for planning purposes, such as for resource allocation and costing of medical supplies for diagnosis and treatment. Dr. Penelope Vounatsou Biostatistics and Computational Sciences Unit Departement für Epidemiologie und Gesundheitswesen Schweizerisches Tropen- und Public-Health-Institut Socinstrasse 57 CH-4051 Basel Phone +41 (0)61 284 81 09 penelope.vounatsou@unibas.ch 205 Vounatsou Penelope Spatio-temporal patterns and forecasting of gender-specific lung and other tobacco-related cancer mortality and morbidity rates in Switzerland (KLS 02393-02-2009) Duration: 01.09.2009 01.09.2012 In Switzerland, lung cancer is the first cause of cancer mortality in men and the second in women. Although mortality is declining in men, in women it is steadily increasing. The Federal Office of Public Health (FOPH) launched the National Program Tobacco 2008 2012, aiming to reduce smoking-related cases of death and disease. Maps of the geographical patterns and trends of lung and other tobacco-related cancers as well as estimates of the disease burden at different regional scales will be important for the design, implementation and evaluation of the National Program Tobacco.

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