ANNUAL REPORT EDUCATIONAL ACTIVITIES 379 STAFF 383

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3 PREFACE ANNUAL REPORT MARIO NEGRI INSTITUTE, MILAN DEPARTMENTS Department of Oncology.. 7 Department of Environmental Health Sciences Department of Neuroscience.. 73 Department of Cardiovascular Research Department of Molecular Biochemistry and Pharmacology Department of Epidemiology Department of Public Health LABORATORIES AND CENTERS Laboratory of Regulatory Policies Centre of Computer Science Engineering. 269 Italian Cochrane Center The Catullo and Daniela Borgomainerio Center 281 Library NEGRI BERGAMO LABORATORIES DEPARTMENTS Department of Molecular Medicine Department of Biomedical Engineering. 309 Laboratory of Biology and Therapy of Metastasis ALDO and CELE DACCO CENTER DEPARTMENT Department of Renal Medicine. 331 LABORATORIES AND CENTERS Rare Diseases Documentation and Research International Relations Office of rare Diseases T he Transplant Research Center. 377 EDUCATIONAL ACTIVITIES 379 STAFF 383 All the staff of the Institute is listed on its website PUBLICATIONS A comprehensive list of the Institute s publications is available on the website Section Publications 1

4 Edited by Isabella Bordogna printed May

5 PREFACE This booklet provides a brief description of the research and training work done at the Mario Negri Institutes in Milan and Bergamo. It is divided by departments, and in some cases by single laboratories. Details of the results are provided in the text itself, so here we shall just draw a few general remarks. This is our first year in the new Milan Headquarters: during this time we devoted most of our efforts improving the new available technologies. Particularly, we have carried out translational research following the mouse clinic patterns. Nuclear magnetic resonance, micro cat scanner, ultrasound, Doppler, photon microscope are some of the methodologies used to do research on human diseases in mice, following the techniques utilized in medical clinic. This will allow to transfer data in more effective ways, to study more in depth and to use a lower number of animals in experimental research. Imaging will play an important role, thanks to the installation of electronic microscopy, of contrast, time- lapse microscopy and atomic force microscopy. New important technologies will also allow us to develop our proteomics research. The tendency nowadays is towards widespread use of molecular biology techniques, especially for studying the mechanism of action of drugs. In vitro studies are an essential basis for thorough investigations although a significant number of in vivo experiments are still needed as this is the only mean we have of validating in vitro findings and establishing models that resemble human diseases as closely as possible. This has led to a substantial increase in the use of transgenic animals. The Institute is still concentrating on its traditional research lines: oncology, neurosciences, cardiovascular and renal diseases, organ transplants, rare diseases with strong cell biology and molecular biochemistry connotations. Significant work has been carried out on the environment and health as a whole. Experimental, clinical and epidemiological research on rare diseases and orphan drugs is growing all the time. The Mario Negri Institute strives to develop a multifaceted approach to all these research themes, ranging from basic research, to pharmacokinetics, pharmacology, controlled clinical trials, epidemiological analysis and whenever possible the epidemiology of services. So far we have published more than articles on peer reviewed scientific journals. If research is to continue young scientists must be continually trained. Working in the laboratory not only gives them an outlet for their ideas, but enables them to obtain worthwhile qualifications by taking part in the Institute s training schemes, which are recognised by the Lombardy Region in Italy, or by working for a Ph.D. awarded by the Open University, UK. Training courses are also available on biomedical statistics, for general practitioners, family pediatricians, and clinical trial nurses. A vital part of the Institute s work involves providing information, at all levels. This is done, in particular, through the Rare Diseases Information Center, the Center for Information on Medicinal Drugs and the Website ( We also provide information to medical doctors, nurses, patients associations and lay people, through the media and through a recently developed website: Because research is going through a very difficult time it is vital to be supported by the Government, by private and public bodies as well as by foundations and private citizens. Silvio Garattini Director 3

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7 Mario Negri INSTITUTE FOR PHARMACOLOGICAL RESEARCH Milan ANNUAL REPORT 2010 departments and laboratories 5

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9 DEPARTMENT OF ONCOLOGY STAFF Chief Maurizio D INCALCI, M.D. Oncological Studies Office and Documentation Scientific Documentalist Stefania FILIPPESCHI, Chemist Laboratory of Cancer Pharmacology Head Biophysics Unit Head Flow Citometry Unit Head Cancer Clinical Pharmacology Unit Head Maurizio D INCALCI, M.D. Paolo UBEZIO, Phys.D. Eugenio ERBA, Biochem.D Massimo ZUCCHETTI, Chem.Pharm.D. Laboratory of Molecular Pharmacology Head DNA Repair Unit Head Massimo BROGGINI, Ph.D. Giovanna DAMIA, M.D. Laboratory of Biology and Treatment of Metastases Head Tumor Angiogenesis Unit Head Unit located in Bergamo Molecular Cancer Therapeutics Unit Head Raffaella GIAVAZZI, Biol.Sci.D., Ph.D. Giulia TARABOLETTI, Biol.Sci.D. Maria Rosa BANI, Biol.Sci.D., Ph.D. 7

10 Laboratory for the development of new pharmacological strategies Head Valter TORRI, M.D. Laboratory of Clinical Trials Head Irene FLORIANI, Dr.Sci.Biol., Dr.Stat., Ph.D. Clinical Trials Informatics and Management Unit Head Davide POLI, Phys.D. Laboratory of Translational and Outcome Research in Oncology Head Gynecology Oncology Unit Head Giovanni APOLONE, M.D. Roldano FOSSATI, M.D. CERP: Center for the Evaluation and Research on Pain Head Giovanni APOLONE, M.D. Oscar CORLI, M.D. Laboratory of Medical Research and Consumer Involvement Head Paola MOSCONI, Biol.Sci.D. 8

11 CURRICULA Maurizio D'Incalci obtained his Medical Degree cum Laude from the University of Milan in After specializing in Pharmacology at the Mario Negri Institute of Milan and in Oncology at the University of Genoa, he worked in the Laboratory of Molecular Pharmacology of the National Cancer Institute in Bethesda, MD, USA. Since 1986 he has been chief of the Laboratory of Cancer Chemotherapy at the Mario Negri Institute and since 1996 he has become chief of the Department of Oncology at the Mario Negri Institute. He has been President of the Pharmacology and Molecular Mechanisms Group of the European Organization for Research and Treatment of Cancer (EORTC). From 1994 to 1997 he was Chairman of the New Drug Development Coordinating Committee and from 1997 to 2000 he was chairman of the Research Division of the EORTC. He has been member of the Board of the EORTC from April 2000 to Since 1995 he is member of the Board of Directors of the Nerina and Mario Mattioli Onlus Foundation. From 1997 he is the Preclinical Coordinator of the Southern Europe New Drug Organization (SENDO) and since 2005 the Chairman of the New Agents Committee (NAC). From 2006 he is president of the Scientific Committee of the Mario Negri Gynecologic Oncology group (MaNGO). From 2007 he is member of the Scientific Committee of the Italian Association for Cancer Research (AIRC). From 2009 he is member of the Board of Directors of the Italian Cancer Society (SIC). From 2010 he is member of the Scientific Committees of the ABO (Application of Biotechnologies in Oncology) Foundation, a national foundation for cancer research, and of the Buzzi Unicem Onlus Foundation for the research, diagnosis and cure of malignant mesothelioma. FHe is on the editorial board of many international cancer-related scientific journals and from September 2000 to December 2010 he is Editor for Experimental Oncology of the European Journal of Cancer. Dr D'Incalci is author of more than 440 papers on cancer chemotherapy published in peer reviewed international journals, and of several chapters in books on cancer chemotherapy. Selected publications Frapolli R., Tamborini E., Virdis E., Bello E., Tarantino E., Marchini S., Grosso F., Sanfilippo R., Gronchi A., Tercero J.C., Peloso G., Casali P., Pilotti S., D Incalci M. Novel models of myxoid liposarcoma xenografts mimicking the biological and pharmacological features of human tumors. Clinical Cancer Res., 16(20): (2010). Germano G., Frapolli R., Simone M., Tavecchio M., Erba E., Pesce S., Pasqualini F., Grosso F., Sanfilippo R., Casali P., Gronchi A., Virdis E., Tarantino E., Pilotti S., Greco A., Nebuloni M., Galmarini C.M., Tercero J.C., Mantovani A., D Incalci M., Allavena P. Anti-tumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells. Cancer Res., 70(6): (2010). Frapolli R, Zucchetti M, Sessa C, Marsoni S, Vigano' L, Locatelli A, Rulli E, Compagnoni A, Bello E, Pisano C, Carminati P, D'Incalci M. Clinical pharmacokinetics of the new oral camptothecin gimatecan: The inter-patient variability is related to α(1)-acid glycoprotein plasma levels. Eur. J. Cancer, 46: (2010) Forni C, Minuzzo M, Virdis E, Tamborini E, Simone M, Tavecchio M, Erba E, Grosso F, Gronchi A, Aman P, Casali P, D'Incalci M, Pilotti S, Mantovani R. Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma tumors. Mol Cancer Ther, 8 : (2009). Marchini S, Mariani P, Chiorino G, Marrazzo E, Bonomi R, Fruscio R, Clivio L, Garbi A, Torri V, Cinquini M, Dell'Anna T, Apolone G, Broggini M, D'Incalci M. Analysis of gene expression in early-stage ovarian cancer Clin Cancer Res, 14 : (2008). Grosso F., Jones R.L. Demetri G.D., Judson I.R., Blay J.Y., Le Cesne A., Sanfilippo R., Casieri P., Collini P., Dileo P., Spreafico C., Stacchiotti S., Tamborini E., Tercero J.C., Jimeno J., D Incalci M., Gronchi A., Fletcher J.A., Pilotti S., Casali P.G. Efficacy of Trabectedin (ET-743) in advanced pre-treated myxoid liposarcomas. Lancet Oncology, 2007; 8: Giovanni Apolone, got his Medical degree in 1982 (Pavia, Italy) and his post-doctoral specializations in Internal Medicine in 1987 (Pavia, Italy) and Pharmacological Research (1992). He is Head of the Laboratory of Translational and Outcome Research. He is also Vice-President of the Ethics Committee of the European Institute of Oncology in Milan (Italy). His main fields of interest are: Methodological, ethical and regulatory aspects of clinical research, with special emphasis on oncology and the cancer pain. Health care evaluation with special emphasis on oncology; Development and validation of case-mix and patient-reported outcome measures; 9

12 Education and health promotion research and programs. He is author or co-author of more than 270 publications, most in International peer-reviewed Journals. Mean Impact Factor, computed on peer-reviewed papers: 3.2. H-index (from ISI-Web of knowledge, March 2010): 30. Number of citations: Average citation per item: Number of papers with >50 citations: 19. Selected publications Greco M T, Corli O, Montanari M, Deandrea S, Zagonel V, Apolone G, CPOR SG Investigators. Epidemiology and pattern of care of Breakthrough cancer Pain (BTcP) in a longitudinal sample of cancer patients. Results from the CPOR- SG. Clin J Pain 2010, e-pub. Mannucci E, Petroni M L, Villanova N, Rotella C M, Apolone G, Marchesini G, QUOVADIS Study Group. Clinical and psychological correlates of health-related quality of life in obese patients. Health Qual Life Outcomes : 90. Knudsen K A, Brunelli C, Kaasa S, Apolone G, Corli O, Montanari M, Fainsinger R, Aass N, Fayers P, Caraceni A, Klepstad P, European Palliative Care Research Collaborative (EPCRC), European Pharmacogenetic Study (EPOS).Which variables are associated with pain intensity and treatment response in advanced cancer patients? Implications for a future classification system for cancer pain. Eur J Pain 2010, e-pub. Gacci M, Corona G, Apolone G, Lanciotti M, Tosi N, Giancane S, Masieri L, Serni S, Maggi M, Carini M. Influence of serum testosterone on urinary continence and sexual activity in patients undergoing radical prostatectomy for clinically localized prostate cancer. Prostate Cancer Prostatic Dis : Tettamanti M, Lucca U, Gandini F, Recchia A, Mosconi P, Apolone G, Nobili A, Tallone M V, Detoma P, Giacomin A, Clerico M, Tempia P, Savoia L, Fasolo G, Ponchio L, Della Porta M G, Riva E. Prevalence, incidence and types of mild anemia in the elderly: the " Health and Anemia" population-based study. Haematologica : Massimo Broggini followed the faculty of Science of the University of Milan, got the specialization in Biochemistry at Mario Negri Institute, and the PhD degree at the Open University, London,UK. He worked in the laboratory of Molecular Pharmacology of the National Cancer Institute of Bethesda, Md, in From 1991 he is the head of the Molecular Pharmacology Unit of the Mario Negri Institute and from 1999 he his the head of the Laboratory of Molecular Pharmacology of the same Institute. His main fields of interest are the study of the mechanism of action of new anticancer agents, the search of altered proteins and genes in human cancer and the study of oncosuppressor genes. He is member of the "Pharmacology and Molecular Mechanisms Group" of the European Organisation for the Research and Treatment of Cancer (EORTC) and of the American Association for Cancer Research. He is in the Editorial board of the European Journal of Cancer. He is author of more than 100 articles published in international journals. Selected publications Floriani I, Garassino MC, Broggini M, Veronese S, Marsoni S, Marabese M, Farina G, Scanni A. Role of cetuximab in the treatment of patients with NSCLC: are we throwing out the baby with the bath water? J Clin Oncol ;28:467. Mazzoletti M, Broggini M. PI3K/AKT/mTOR inhibitors in ovarian cancer. Curr Med Chem. 2010;17(36): Sala G, Dituri F, Raimondi C, Previdi S, Maffucci T, Mazzoletti M, Rossi C, Iezzi M, Lattanzio R, Piantelli M, Iacobelli S, Broggini M, Falasca M. Phospholipase Cgamma1 is required for metastasis development and progression. Cancer Res Dec 15;68(24): Marrazzo E, Marchini S, Tavecchio M, Alberio T, Previdi S, Erba E, Rotter V, Broggini M. The expression of the DeltaNp73beta isoform of p73 leads to tetraploidy. Eur J Cancer Feb;45(3): Epub 2008 Nov 12. Falasca M, Chiozzotto D, Godage HY, Mazzoletti M, Riley AM, Previdi S, Potter BV, Broggini M, Maffucci T. A novel inhibitor of the PI3K/Akt pathway based on the structure of inositol 1,3,4,5,6-pentakisphosphate. Br J Cancer Jan 5;102(1): PubMed PMID: ; Ganzinelli M, Carrassa L, Crippa F, Tavecchio M, Broggini M, Damia G. Checkpoint kinase 1 down-regulation by an inducible small interfering RNA expression system sensitized in vivo tumors to treatment with 5-fluorouracil. Clin Cancer Res Aug 15;14(16): Irene Floriani got her degree in Biological Sciences at the University of Milan in 1988, her degree in Biostatistics and Experimental Statistics at the University of Milan in 2003 and her phd in Life Sciences at Open University of London (UK) in After ten-year experience in pharmaceutical industry, in 2002 she became Head of the Biometry and Data Management Unit of the Laboratory of Clinical Research in Oncology and since 2006 she is Head of Laboratory of Clinical Trials. She is President of the Ethics Committee of the Ospedale Sant Anna of Como, Vice-President of that of the Fondazione IRCCS Istituto Neurologico Carlo Besta of Milan, and member of further two Ethics Committees. Her main fields of interest are: statistical aspects of methodology of clinical research with focus on Controlled Clinical Trials in Oncology; Systematic Overview of the medical literature and Methodological aspects of 10

13 diagnostic test evaluation. Selected publications Floriani I, Garattini S, Torri V. Looking for efficiency rather than efficacy in randomized controlled trials in oncology. Ann Oncol Jul; 21(7): Luciani A, Ascione G, Bertuzzi C, Marussi D, Codecà C, Di Maria G, Caldiera SE, Floriani I, Zonato S, Ferrari D, Foa P. Detecting disabilities in older patients with cancer: comparison between comprehensive geriatric assessment and vulnerable elders survey-13. J Clin Oncol Apr 20;28(12): Floriani I, Torri V, Rulli E, Garavaglia D, Compagnoni A, Salvolini L, Giovagnoni A. Performance of imaging modalities in diagnosis of liver metastases from colorectal cancer: a systematic cancer: a systematic review and metaanalysis. J Magn Reson Imaging Jan;31(1): Floriani I, Garassino MC, Broggini M, Veronese S, Marsoni S, Marabese M, Farina G, Scanni A. Role of Cetuximab in the Treatment of Patients With NSCLC: Are We Throwing out the Baby With the Bath Water? J Clin Oncol Jun 28. Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, Santini D, Masi G, Stasi I, Canestrari E, Rulli E, Floriani I, Bencardino K, Galluccio N, Catalano V, Tonini G, Magnani M, Fontanini G, Basolo F, Falcone A, Graziano F. KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer. Br J Cancer : Floriani I, Santini D, Torri V, Cremolini C, Falcone A, Loupakis F. Do we need biopsies of metastases for colorectal cancer patients? Br J Cancer : Raffaella Giavazzi got her Biological Sciences degree (1979) at the University of Milan, and her PhD in Pharmacology at the Mario Negri Institute of Milan (1984), followed by a specialization in pharmacology (1994) at the University of Milan. From 1981 to 1983 she was a Fellow in the Cancer Metastasis and Treatment Laboratory, NCI-FCRDC, Frederick, MD, and from 1983 to 1985 Assistant Professor at the Department of Cell Biology of M.D. Anderson Hospital and Tumour Institute, University of Texas System Cancer Centre in Houston, TX. Raffaella Giavazzi s research interests are in the field of tumour biology and pharmacology. Specifically, she is studying aspects related to the metastatic process and angiogenesis. She is involved in the preclinical evaluation of new therapeutic strategies against cancer focusing on the angiogenesis inhibitors and combination therapies. From 1986 to 1993 she was Head of the Cancer Metastasis Treatment Unit and since 1993 she has been the Head of the Laboratory of Biology and Treatment of Metastasis at Mario Negri Institute for Pharmacological Research. She is also adjutant Professor in Oncology, Medical School-University of Brescia, member of the Teaching Committee for the PhD course in Physiology-Pharmacology-Molecular and Cellular Toxicology-University of Siena, member of the Executive Committee at SENDO (Southern Europe New Drug Development Organization) and member of the Executive Committee of the European Association for Cancer Research (EACR). She was consulting scientist for the NCI-Drug Therapeutics Program, USA ( ); She is a member of the American Association for Cancer Research (AACR), International Metastases Research Society, EORTC-Screening and Pharmacology Group, European Association for Cancer Research (EACR), Italian Cancer Society (SIC) of which she was President ( ). She is on the Editorial Board of international scientific journals such as the European Journal of Cancer, Journal of Clinical & Experimental Metastasis, and The International Journal of Biological Markers. She has published approximately 200 articles on peer reviewed scientific journals. Selected publications Borgia B., Rösli C., Fugmann T., Schliemann C., Cesca M., Neri D., Giavazzi R. A proteomic approach for the identification of vascular markers of liver metastasis. Cancer Research, 70(1):309-18, Rösli C., Borgia B., Schliemann C., Gunther M., Wunderli-Allenspach H., Giavazzi R., Neri D. Comparative analysis of the membrane protome of closely related metastatic and non-metastatic tumor cells. Cancer Research, 69(13): , Cesca M., Frapolli R., Berndt A., Scarlato V., Richter P., Kosmehl H., D Inclaci M., Ryan A.J., Giavazzi R. The effects of vandetanib on paclitaxel tumor distribution and antitumor activity in a xenograft model of human ovarian carcinoma. Neoplasia, 11(11): , Ghilardi C., Chiorino G., Dossi R., Nagy Z., Giavazzi R., Bani M.R. Identification of novel vascular markers through gene expression profiling of tumor-derived endothelium. BMC Genomics, 30(9), 201, Giavazzi R., Bani M.R.,Taraboletti G.: Tumor host interaction in the optimization of paclitaxel-based combination therapies with vascular targeting compounds. Cancer Metastasis Rev. 26:481 88, 2007 Naumova E., Ubezio P., Garofalo A., Borsotti P., Cassis L., Riccardi E., Scanziani E., Eccles S.A., Bani M.R., Giavazzi R. The vascular targeting property of paclitaxel is enhanced by SU6668, a receptor tyrosine kinase inhibitor, causing apoptosis of endothelial cells and inhibition of angiogenesis. Clin. Cancer Research 12(6): ,

14 Rybak J.N., Ettore A., Kaissling B., Giavazzi R., Neri D., Elia G. In vivo protein biotinylation for identification of organ-specific antigens accessible from the vasculature. Nature Methods 2(4):291-98, Paola Mosconi got her Biological Science degree (Milan 1982) and the specialisation in Pharmacological Research (Milan 1984). Paola Mosconi is involved in several national projects on issues pertaining the patient involvement in care aspects and outcome research. She published more than 300 articles in leading national and international journals (111), as well as books on issues related to her main areas of interest. Significant experiences has been coordinated: development of research projects and strategies to involve patients or consumer associations in health debate, and clinical research, consensus conferences training for consumers on quality of information, and methodological aspects of clinical research; studies for estimate the type of information on diseases and treatments received by patients, mainly in cancer patients; set-up of websites targeted on consumers/patients projects on the assessment of Quality of Life in randomised clinical trials or in epidemiological survey; translation and cultural adaptation of questionnaires for Quality of Life; evaluation of the consumers satisfaction with the health services and the care received. Paola Mosconi has participated as teacher, or coordinator, to the realization of training course on Methodological aspects of clinical research or Evaluation of quality of life for health care professionals and representatives of voluntary associations. Major present functions - President of the Ethical Committees of the AUSL Bologna - Elected member of Associazione per la Ricerca sulla Efficacia della Assistenza Sanitaria - Italian Cochrane Centre - Founding member of Europa Donna Italia, the European breast cancer coalition Selected publications Mosconi P, Colombo C Fostering a strategic alliance between patients associations and health care professionals J Ambul Care Manage 2010, 33 (3): Tettamanti M, Lucca U, Gandini F, Recchia A, Mosconi P, Apolone G, Nobili A, Tallone MV, Detoma P, Giacomin A, Clerico M, Tempia P, Savoia L, Fasolo G, Ponchio L, Della Porta MG, Riva E Prevalence, incidence and types of mild anemia in the elderly: the "Health and Anemia" population-based study Haematologica 2010; 95(11): Mosconi P, Donati S, Colombo C, Mele A, Liberati A, Satolli R. The Consensus Conference WorkingGroup. Informing women about hormone replacement therapy: the Consensus conference statement. BMC Woman Health Journal 2009; 9:14 doi: / Mosconi P, Colombo C, Satolli R, Liberati A. PartecipaSalute, an Italian project to involve lay people, patients associations and scientific-medical representatives on the health debate. Health Expectations 10: , Mosconi P, Poli P, Giolo A, Apolone G. How health consumers feel about clinical research: a questionnaire survey. European Journal of Public Health 15: , Mosconi P, Buchanan M, Kyriakides S, Fernandez-Marcos A, Horvatin J, O'Connell D, Zernik N, on behalf of EUROPA DONNA. EUROPA DONNA: has strength in its heterogeneity. European J Cancer 40: , Valter Torri got his Medical degree in 1985 and the specialization in medical Oncology in 1989 at the University of Milano. Education: 1985: MD Degree with full honors cum Laude, University of Milano; 1988 Post-Doctoral Degree in Pharmacological Research, Mario Negri Institute, Milano; 1989 Post-Doctoral Degree in Medical Oncology, University of Milano; Research Fellow at the Biometric Research Branch of Cancer Treatment Evaluation Program, NCI, Bethesda, MD (USA) Areas of Interest: Statistical aspects of clinical research methodology with focus on Controlled Clinical Trials in Oncology; Systematic Overview of the medical literature; Methodological aspects of diagnostic test evaluation. Present Position: Head of Laboratory of Clinical Research In Oncology, Oncology Department, Mario 12

15 Negri Institute, Milano. Chronology of Professional Appointments: : Clinical research Fellow in Internal Medicine at the University Hospital, University of Milan; : Research assistant at the Clinical Trial Unit of the Laboratory of Clinical Epidemiology, Mario Negri Institute for Pharmacological Research, Milano; : Research fellow at the Biometric Research Branch of Cancer Treatment Evaluation Program, NCI, Bethesda, MD (USA); 1994: Head of Biometric Unit of the Laboratory of Cancer Clinical Epidemiology, Oncology Department, Mario Negri Institute for Pharmacological Research, Milano, Italy; 1995 Vice Director of the Italian Cochrane Center; 2001: Head of Laboratory of Clinical Research In Oncology, Oncology Department, Mario Negri Institute, Milano. 2006: Head of Laboratory for the development of new pharmacological strategies, Oncology Department, Mario Negri Institute, Milano. Member of Consiglio Direttivo Nazionale dell Associazione Italiana di Oncologia Medica Member of Independent data monitoring committee of International Randomised Clinical trials in NSCLC and ovarian carcinoma Co-author of more than 160paper published on peer reviewed journals and of 5 chapters of scientific books relative to clinical research methodology for therapeutic and diagnostic studies. Selected publications Rossi A, Garassino MC, Cinquini M, Sburlati P, Di Maio M, Farina G, Gridelli C, Torri V. Maintenance or consolidation therapy in small-cell lung cancer: a systematic review and meta-analysis. Lung Cancer. 201;70(2): Sargent DJ, Marsoni S, Monges G, Thibodeau SN, Labianca R, Hamilton SR, French AJ, Kabat B, Foster NR, Torri V, Ribic C, Grothey A, Moore M, Zaniboni A, Seitz JF, Sinicrope F, Gallinger S. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol Jul 10;28(20): Epub 2010 May 24. Erratum in: J Clin Oncol ; 28(30): Floriani I, Garattini S, Torri V. Looking for efficiency rather than efficacy in randomized controlled trials in oncology. Ann Oncol (7): Epub 2010 May 25. PubMed PMID: Laghi L, Bianchi P, Miranda E, Balladore E, Pacetti V, Grizzi F, Allavena P, Torri V, Repici A, Santoro A, Mantovani A, Roncalli M, Malesci A. CD3+ cells at the invasive margin of deeply invading (pt3-t4) colorectal cancer and risk of postsurgical metastasis: a longitudinal study. Lancet Oncol. 2009; 10 (9): Garassino MC, Borgonovo K, Rossi A, Mancuso A, Martelli O, Tinazzi A, Di Cosimo S, La Verde N, Sburlati P, Bianchi C, Farina G, Torri V. Biological and clinical features in predicting efficacy of epidermal growth factor receptor tyrosine kinase inhibitors: a systematic review and meta-analysis. Anticancer Res. 2009; 29 (7): Torri V: Clinical trials and data management In: Oxford textbook of oncology, 2nd. ed. Vol. 1. Oxford Univ. Press, Oxford; 2002 : Maria Rosa Bani got her Biological Sciences degree at the University of Milan in 1998 attaining the Italian Government Qualification to practice as Biologist in She obtained the specialization in Pharmacological Research from the Department of Education of the Regional Government of Lombardia in 1991 and the specialization in Biomedical Research from the Department of Education of the Regional Government of Abruzzo in In 2005 she was awarded the degree of Doctor of Philosophy (PhD), Discipline of Life Sciences of the Open University Research School (UK). From 1991 to 1995 she was a Post Doctoral Fellow at the Cancer Research Division, Sunnybrook Health Science Centre, University of Toronto (Canada); from 2000 to 2001 she was Guest Scientist at the Advance Technology Centre, National Cancer Institute, National Institute of Health (USA). From 1996, she was a Fellow Research Scientist at the Mario Negri Institute for Pharmacological Research, Laboratory of Biology and Treatment of Metastasis and she became a staff research scientist in Since 2004 she was appointed Head of the Molecular Cancer Therapeutics Unit in the same laboratory. She has been the Scientific Manager of STROMA (since 2004) and ADAMANT (since2008), two Integrated Projects funded in the 6 th and 7 th Framework Programs of the European Commission. She is a member of the American Association for Cancer Research (AACR), the European Association for Cancer Research (EACR) and the Italian Cancer Society (SIC). Maria Rosa Bani research interests are in the field of cancer biology and therapeutics, with a focus on molecular studies of the malignant progression and on the preclinical efficacy of therapeutics modalities. She is co-author of 36 peer reviewed publications, 2 book chapters and 67 abstracts of which 15 selected for oral presentations at international meetings. Selected publications Silini A., Ghilardi C., Ardinghi C., Bernasconi S., Carraro F., Naldini A., Bani M.R., Giavazzi R. Protease-activated receptor-1 (PAR-1) promotes the motility of human melanomas and is associated to their metastatic phenotype. Clinical Experimental Metastasis, 27 (1) : 43-53,

16 Ghilardi C., Chiorino G., Dossi R., Nagy Z., Giavazzi R., Bani M.R. Identification of novel vascular markers through gene expression profiling of tumor-derived endothelium. BMC Genomics, 30(9), 201, Giavazzi R., Bani M.R.,Taraboletti G.: Tumor host interaction in the optimization of paclitaxel-based combination therapies with vascular targeting compounds. Cancer Metastasis Rev. 26:481 88, Naumova E., Ubezio P., Garofalo A., Borsotti P., Cassis L., Riccardi E., Scanziani E., Eccles S.A., Bani M.R. & Giavazzi R. The vascular targeting property of paclitaxel is enhanced by SU6668, a receptor tyrosine kinase inhibitor, causing apoptosis of endothelial cells and inhibition of angiogenesis. Clinical Cancer Research 12: , Bani M.R., Nicoletti M.I., Alkharouf N.W., Ghilardi C., Petersen D., Erba E., Sausville E.A., Liu E.T. and Giavazzi R. Gene expression correlating with response to paclitaxel in ovarian carcinoma xenografts. Molecular Cancer Therapeutics 3: , Taraboletti G., Sonzogni L., Vergani V., Hosseini G., Ceruti R., Ghilardi C., Bastone A., Toschi E., Borsotti P., Scanziani E., Giavazzi R., Pepper M.S., Stetler-Stevenson W.G., Bani M.R. Post-transcriptional stimulation of endothelial cell matrix metalloproteinases 2 and 1 by endothelioma cells. Experimental Cell Research 258 : , Giovanna Damia obtained her Medical Degree cum Laude from the University of Milan in After specializing in Pharmacology at the Mario Negri Institute of Milan and in Oncology at the University of Milan, she worked as a post-doctoral fellow in the Laboratory of Experimental Immunology of the National Cancer Institute, Frederick, USA. She worked as a research fellow in the Laboratory of Cancer Chemotherapy at the Mario Negri Institute and since April 2003 she has become chief of the DNA Repair Unit at the Mario Negri Institute. From 1992 to1995 she has been consultant of the General Secretariat of the Progetto Finalizzato CNR "Applicazioni Cliniche della Ricerca Oncologica". Since September 2005 she is Deputy Editor for Experimental Oncology of the European Journal of Cancer. Her main fields of interest are: mechanism of action of anticancer drugs, cell cycle checkpoints and natural compounds. Selected publications Damia G, D'Incalci M. Genetic instability influences drug response in cancer cells. Curr Drug Targets Oct;11(10): Carrassa L, Montelatici E, Lazzari L, Zangrossi S, Simone M, Broggini M, Damia. G. Role of Chk1 in the differentiation program of hematopoietic stem cells. Cell Mol Life Sci May;67(10): Carrassa L, Sanchez Y, Erba E, Damia G. U2OS cells lacking Chk1 undergo aberrant mitosis and fail to activate the spindle checkpoint. J Cell Mol Med Aug;13(8A): Ganzinelli M, Carrassa L, Crippa F, Tavecchio M, Broggini M, Damia G. Checkpoint kinase 1 down-regulation by an inducible small interfering RNA expression system sensitized in vivo tumors to treatment with 5-fluorouracil. Clin Cancer Res Aug 15;14(16): Tavecchio M, Simone M, Erba E, Chiolo I, Liberi G, Foiani M, D'Incalci M, Damia G. Role of homologous recombination in trabectedin-induced DNA damage. Eur J Cancer Mar;44(4): Epub 2008 Feb 19. Damia G, D'Incalci M. Targeting DNA repair as a promising approach in cancer therapy. Eur J Cancer Aug;43(12): Eugenio Erba has obtained his Biological and Biochemistry Analysis Degree at the University of Urbino. He worked as a research fellow in the Laboratory of Cancer Chemotherapy at the Mario Negri Institute and since 1984 he is head of the Flow Cytometry Unit in the Department of Oncology at the Mario Negri Institute of Milan. He has worked as a visiting fellow in the Department of Istochemistry and Cytochemistry of the University of Leiden, The Netherlands in Since 1997 he is Teacher of Post-Graduate Studies in Cytometry at the University of Milan and Co-ordinator and Teacher of Post- Graduate Studies in Cytometry for the Italian Cytometry Group. He has been President of the Italian Cytometry Group from 1999 to Since 2001 he is member of the Executive Board of the Italian Cytometry Group. Scientific areas of interest: studies on the mechanism of action of different compounds with provided antitumoral activity evaluating the mechanism of cell death and cell cycle phase perturbations induced on different human cancer cell lines by using flow cytometry. Co-ordinator of working-group in a quality control study on flow cytometric DNA content analysis in human tumors. Selected publications Urru S.A.M., Veglianese P., De Luigi A., Fumagalli E., Erba E., Gonella Diaza R., Carrà A., Davoli E., Borsello T., Forloni G., Pengo N., Monzani E., Cascio P., Cenci S., Sitia R., Salmona M. A new fluorogenic peptide determines proteasome activity in single cells. J.Med.Chem., 53: (2010). Germano G., Frapolli R., Simone M., Tavecchio M., Erba E., Pesce S., Pasqualini F., Grosso F., Sanfilippo R., Casali P., Gronchi A., Virdis E., Tarantino E., Pilotti S., Greco A., Nebuloni M., Galmarini C.M., Tercero J.C., Mantovani A., D Incalci M., Allavena P. Anti-tumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells. Cancer Res., 70(6): (2010). 14

17 C. Forni, M Minuzzo, E. Virdis, E. Tamburini, M. Simone, M. Tavecchio, E. Erba, F. Grosso, A. Gronchi, P.Aman, P. Casali, M. D Incalci, S. Pilotti, R. Mantovani. Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma tumors. Mol. Ca. Ther. 8(2), , 2009 E. Marrazzo, S. Marchini, M. Tavecchio, T. Alberio, S. Previdi, E. Erba, V. Rotter, M. Broggini The expression of the ΔNp73β isoform of p73 leads to tetraploidy. Eur J Ca 45, , 2009 M.Tavecchio, M. Simone, E.Erba, I. Chiolo, G. Liberi, M. Foiani, M. D Incalci, G. Damia. Role of homologous recombination in trabectedin-induced DNA damage. Eur. J. Ca 44: (2008) Paulis M., Bensi M., Orioli D., Mondello C., Mazzini G., D Incalci M., Falcioni C., Radaelli E., Erba E., Raimondi E., De Carli L. Transfer of a Human Chromosomal Vector from a Hamster Cell Line to a Mouse Embryonic Stem Cell Line. Stem Cell, 25: (2007) Roldano Fossati got his Medical Degree cum Laude from the University of Milan in 1980, his Post- Doctoral Degree in Endocrinolgy cum Laude from the University of Verona in 1983 and his Post- Doctoral Degree in Medical Statistics from the University of Milan in He has been consultant at the Mario Negri Institute since 1983 and, at present, he is head of the Gynecology and Oncology Unit of the Laboratory of Translational and Outcome Research. Areas of Interest: Statistical and methodologic aspects of clinical research with focus on Controlled Clinical Trials in Oncology; Systematic Overview of the medical literature. Selected publications Hogberg T, Signorelli M, de Oliveira CF, Fossati R, Lissoni AA, Sorbe B, Andersson H, Grenman S, Lundgren C, Rosenberg P, Boman K, Tholander B, Scambia G, Reed N, Cormio G, Tognon G, Clarke J, Sawicki T, Zola P, Kristensen G. Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies. Eur J Cancer Sep;46(13): Epub 2010 Jul 7. Signorelli M, Lissoni AA, Cormio G, Katsaros D, Pellegrino A, Selvaggi L, Ghezzi F, Scambia G, Zola P, Grassi R, Milani R, Giannice R, Caspani G, Mangioni C, Floriani I, Rulli E, Fossati R. Modified Radical Hysterectomy Versus Extrafascial Hysterectomy in the Treatment of Stage I Endometrial Cancer: Results From the ILIADE Randomized Study. Ann Surg Oncol Oct 16 Andrea Alberto Lissoni, Nicoletta Colombo, Antonio Pellegrino, Gabriella Parma, Paolo Zola, Dionyssios Katsaros, Stefania Chiari, Alessandro Buda, Fabio Landoni, Michele Peiretti, Tiziana Dell Anna, Robert Fruscio, Mauro Signorelli, Roberto Grassi, Irene Floriani, Roldano Fossati, Valter Torri, Eliana Rulli. A phase II, randomized trial of neoadjuvant chemotherapy comparing a three-drug combination of paclitaxel, ifosfamide and cisplatin (TIP) versus paclitaxel and cisplatin (TP) followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the Snap- 02 Italian Collaborative Study. Annals of Oncology, 20: ;2009 Fruscio R, Colombo N, Lissoni AA, Garbi A, Fossati R, Ieda' N, Torri V, Mangioni C.A phase II randomised clinical trial comparing cisplatin, paclitaxel and ifosfamide with cisplatin, paclitaxel and epirubicin in newly diagnosed advanced epithelial ovarian cancer: long-term survival analysis. Br J Cancer Feb 5; Maggi R, Lissoni A, Spina F, Melpignano M, Zola P, Favalli G, Colombo A, Fossati R. Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial. Br J Cancer Aug 7;95(3): Maggioni A, Benedetti Panici P, Dell'anna T, Landoni F, Lissoni A, Pellegrino A, Rossi RS, Chiari S, Campagnutta E, Greggi S, Angioli R, Manci N, Calcagno M, Scambia G, Fossati R, Floriani I, Torri V, Grassi R, Mangioni C.Randomised study of systematic lymphadenectomy in patients with epithelial ovarian cancer macroscopically confined to the pelvis. Br J Cancer Sep 18;95(6): Davide Poli got his degree in Physics at the University of Milan in 2007 and his specialization in Biochemical Research Technician" at the Mario Negri Institute for Pharmacological Research in Since 2010 he is Head of Clinical Trials Informatics and Management Unit of the Clinical Trials Laboratory. His areas of interest are: design of ecrf in Clinical Trials, new electronic aspects of Clinical Research especially towards technologies of Web-based Electronic Data Capture, methodology and data management aspects in Clinical Research. Selected Publications Ocular Hypertension Treatment Study Group, European Glaucoma Prevention Study Group (EGPS), Poli D The accuracy and clinical application of predictive models for primary open-angle glaucoma in ocular hypertensive individuals Ophthalmology, Volume 115, Number 11 pp , November 2008 Porcu L, Poli D, Torri V, Rulli E, Cropalato di Tullio M, Cinquini M, Bajetta E, Labianca R, Di Costanzo F, Nitti D, Floriani I Impact of recent legislative bills regarding clinical research on Italian ethics committee activity Journal of Medical Ethics 2008, Volume 34, pp Gordon MO, Torri V. Miglior S, Beiser JA, Floriani I, Miller JP, Gao F, Adamsons I, Poli D, D'Agostino RB, Kass MA. A validated prediction model for the development of primary open-angle glaucoma in individuals with ocular hypertension. 15

18 Ophthalmology, Volume 114, Number 1, pp , January 2007 The European Glaucoma Prevention Study (EGPS) Group, Poli D Results of the European Glaucoma Prevention Study. Ophthalmology, Volume 112, Number 3, pp , March 2005 Icon, Torri V, Floriani I, Poli D, Santillo M, Buda A Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: The ICON4/AGO-OVAR-2.2 Trial. Lancet 2003; 361: Giulia Taraboletti got her degree cum laude in Biological Sciences at the University of Pavia (Pavia, Italy) in 1983, and the specialization in Pharmacological Research at the Mario Negri Institute, Milano, Italy in From 1986 to 1988 she was a post-doctoral fellow at the Laboratory of Pathology, NCI, NIH, Bethesda, MD, and from research scientist at Mario Negri Institute in Bergamo, Italy. Since 1995 she is Head of the Unit of Tumor Angiogenesis, at Mario Negri Institute, in Bergamo. Research interests include tumor angiogenesis, endogenous inhibitors of angiogenesis (thrombospondin-1) and preclinical studies of antiangiogenic and vascular disrupting compounds, including tubulin-targeting agents. She is member of Metatasis Research Society (MRS), American Association for Cancer Research (AACR), European Association for Cancer Research (EACR), and the Italian Society of Oncology (SIC). She is on the editorial board of European Journal of Cancer and Current Cancer Therapy Reviews. Selected publications Colombo G, Margosio B, Ragona L, Neves M, Bonifacio S, Annis DS, Stravalaci M, Tomaselli S, Giavazzi R, Rusnati M, Presta M, Zetta L, Mosher DF, Ribatti D, Gobbi M, Taraboletti G. Non-peptidic thrombospondin-1-mimics as fibroblast growth factor-2 inhibitors: an integrated strategy for the development of new antiangiogenic compounds. J Biol Chem, 285: , Bonezzi K., Taraboletti G., Borsotti P., Bellina F., Rossi R., Giavazzi R. Vascular disrupting activity of tubulin-binding 1,5-diaryl-1H-imidazoles. J Med Chem 52, , Margosio B, Rusnati M, Bonezzi K, Cordes B-lA, Annis DS, Urbinati C, Giavazzi R, Presta M, Ribatti D, Mosher DF, and Taraboletti G. Fibroblast growth factor-2 binding to the thrombospondin-1 type III repeats, a novel antiangiogenic domain. Int J Biochem Cell Biol 40: , Giavazzi R., Bani M.R.,Taraboletti G. Tumor host interaction in the optimization of paclitaxel-based combination therapies with vascular targeting compounds. Cancer Metastasis Rev, 26:481 88, Martinelli M., Bonezzi K., Riccardi E., Kuhn E., Frapolli R., Zucchetti M., Ryan A.J., Taraboletti G., Giavazzi R. Sequence dependent antitumour efficacy of the vascular disrupting agent ZD6126 in combination with paclitaxel. Br J Cancer 97:888-94, Margosio B., Marchetti D., Vergani V., Giavazzi R., Rusnati M., Presta M., and Taraboletti G. Thrombospondin-1 as a scavenger for matrix-associated fibroblast growth factor-2. Blood 102: , Paolo Ubezio got his B.Sc. degree in Physics at the University of Milan, in 1982, and the specialisation in Pharmacological Research Specialist" at the Mario Negri Institute for Pharmacological Research in Main activities are: i) Computer simulation of tumor proliferation during/after treatments using models based on the cell cycle; ii) Development of new methods and data analysis tools in flow cytometry and in time-lapse imaging of living cells; iii) Optimization of anticancer drug scheduling. Since 1991 is Head of the Unit of Biophysics at the Mario Negri Institute Selected publications Ubezio, P.; Lupi, M., Branduardi, D.; Cappella, P., Cavallini, E., Colombo, V., Matera, G., Natoli, C., Tomasoni, D., D Incalci, M. (2009) Quantitative assessment of the complex dynamics of G1, S and G2M checkpoint activities. Cancer Res. 69: Valentini, G., D Andrea, C., Ferrari, R., Pifferi, A., Cubeddu, R., Martinelli, M., Natoli, C., Ubezio, P. and Giavazzi R. (2008) In-vivo measurement of vascular modulation in experimental tumors using a fluorescent contrast agent. Photochem. Photobiol. 84: Ubezio, P. and Cameron, D. (2008) Cell killing and resistance in pre-operative breast cancer chemotherapy. BMC Cancer 8:201. Basse, B., Ubezio, P. (2007) A generalised age and phase structured model of human tumour cell populations both umperturbed and exposed to a range of cancer therapies. Bull. Math. Biol. 69: Lupi, M., Matera, G., Natoli, C., Colombo, V., Ubezio, P. (2007) The Contribution of p53 in the Dynamics of Cell Cycle Response to DNA Damage Interpreted by a Mathematical Model. Cell Cycle 6: Lupi, M., Matera, G., Branduardi, D., D'Incalci M. and Ubezio, P. (2004) Cytostatic and cytotoxic effects of topotecan decoded by a novel mathematical simulation approach. Cancer Res. 64:

19 Massimo Zucchetti obtained his Chem. Pharm. Degree from the University of Milan in After specializing in Pharmacology at the Mario Negri Institute of Milan (1988), he worked in the Laboratory of Clinical Pharmacology of Department of Oncology at San Giovanni Hospital, Bellinzona, Switzerland ( ). Since 1996 he has been chief of the Cancer Clinical Pharmacology Unit at the Mario Negri Institute. He is member of the Pharmacology and Molecular Mechanisms Group of the European Organization for Research and Treatment of Cancer (EORTC) from 1988 up to date. His main field of interest are: - Clinical pharmacology, phase I and Phase II studies - Analysis of drugs, development of new analytical method, pharmacokinetic and pharmacodynamic studies in humans in GCP and GLP conditions - Pharmacokinetic, toxicokinetic and metabolic studies in animals - Pharmacokinetic drug interaction Dr Zucchetti is author of more than 90 papers on pre-clinical and clinical cancer chemotherapy published in peer reviewed international journals. Selected publications Sala F., Marangon E., Bagnati R., Livi V., Cereda R., D Incalci M., Zucchetti M. Development and validation of a HPLC-MS/MS method for the determination of the novel proteasome inhibitor CEP in human plasma and its application in a clinical pharmacokinetic study. J Mass Spectrom. 2010; 45: Frapolli R., Zucchetti M., Sessa C., Marsoni SA., Viganò L., Locatelli A., Rulli E., Compagnoni A., Bello E., Pisano C., Carminati P., D Incalci M. Clinical pharmacokinetics of the new oral camptothecin gimatecan: the intra-patients variability is related to α1-acid glycoprotein plasma levels. Eur J Cancer 2010, 66: Sala F., Zucchetti M., Bagnati R., D Incalci M., Pace S., Capocasa F., Marangon E. Development and validation of a HPLC-MS/MS m,ethod for the determination of ST1926, a novel oral antitumor agent, adamantyl retinoid derivative, in human plasma of patients partecipatig in a phase I study. J Chromatogr B: Anal. Tecnol. Biomed. Life Sci. 2009; 31: Gambacorti-Passerini CB, Tornaghi L, Marangon E, Franceschino A, Pogliani EM, D'Incalci M, Zucchetti M.. Imatinib concentrations in human milk Blood Feb 15;109(4):1790. Marangon E, Sala F, Caffo O, Galligioni E, D'Incalci M, Zucchetti M. Simultaneous determination of gemcitabine and its main metabolite, dfdu, in plasma of patients with advanced non-small-cell lung cancer by high-performance liquid chromatography-tandem mass spectrometry. J Mass Spectrom Feb;43(2): Frapolli R., Marangon E., Zaffaroni M., Colombo T., Falcioni C., Bagnati R., Simone M., D Incalci M., Manzotti C., Fontana G., Morazzoni P., Zucchetti M. Pharmacokinetics and metabolism in mice of IDN 5390 (13-(N-Boc-3-ibutylisoserinoyl)-C-7,8-seco-10-deacetylbaccatin III), a new oral C-seco-taxane derivative with antiangiogenic property effective on paclitaxel-resistant tumors. Drug Metabolism and Disposition, 34(12): (2006). ACTIVITIES The Oncology Department comprises three preclinical experimental laboratories (Laboratory of Cancer Pharmacology, Laboratory of Molecular Pharmacology and Laboratory of Biology and Treatment of Metastases) and four laboratories dealing with clinical research and clinical trials (Laboratory for the Development of New Pharmacological Strategies, Laboratory of Clinical Trials, Laboratory of Translational and Outcome Research in Oncology and Laboratory for Medical Research and Consumer Involvement). The Oncology department hosts the coordination center of two networks of hospitals that carry on clinical research in gynecologic cancer (MaNGO: Mario Negri Gynecologic Oncology) and in cancer pain (CPOR-SG: Cancer Pain Outcome Research Study Group) and a center for cancer pain assessment and research (CERP:Center for the Evaluation and Research on Pain). In some cases research projects are carried out by single laboratories or research units, in other cases by collaborations between different laboratories of the Oncology Department or other departments, or other groups outside the Institute (see National and International Collaborations). Preclinical laboratories focus on the discovery and development of new antitumor and antimetastatic drugs and their new combinations; on tumor biology, not only to acquire new scientific knowledge, but particularly as a base for more selective therapeutic approaches and to identify and evaluate experimental models for discovering and studying new drugs or treatments. Clinical new drug development involves close participation in the activity of SENDO (Southern 17

20 Europe New Drug Organization) and studies driven by the Laboratory of Cancer Pharmacology, the Laboratory of Molecular Pharmacology and the Laboratory of Biology and Treatment of Metastases. The Laboratory for the Development of New Pharmacological Strategies, the Laboratory of Clinical Trials, the Laboratory of Translational and Outcome Research in Oncology and the Laboratory for Medical Research and Consumer Involvement are involved in the evaluation of the effects of new therapeutic modalities in phase I/II and in phase III comparative and effectiveness outcome studies. Outcome Research implies organizing trials to clarify the results of certain health care practices and interventions in clinical practice. Observational (surveys) and outcome research (effectiveness) studies are carried out, in collaboration with regional and national health authorities and other scientific associations. At the preclinical and clinical level there are studies of various human tumors, with particular emphasis on ovarian tumors and more recently on soft tissue sarcomas. MAIN FINDINGS At nanomolar concentrations, Trabectedin affects the regulatory mechanisms of the transcription. Cells that are deficient in Homologous Recombination DNA Repair -e.g. with mutations of BRCA1 or BRCA2 genes- are hypersensitive to the drug Nucleotide excision repair deficient cells that are hypersensitive to UV rays and to other DNA damaging drugs are resistant to Trabectedin. The selective activity of Trabectedin against human myxoid liposarcoma appears related to the drug ability to modulate the transcription of genes involved in adipocytic differentiation. Trabectedin modulates the transcription of genes involved in pro-inflammatory mechanisms that are potentially relevant for tumor growth and progression and inhibits the production of cytokines and chemokines by macrophages that are tumor associated. New sarcoma experimental models have been obtained. They will be useful to investigate new drugs for these diseases. Use of mathematical models of tumor growth and anticancer treatment to interpret experimental data and to manage the complexity of underlying biological phenomena. A new method enabling to perform dynamical measures of cell cycle checkpoint activities in response to anticancer treatments. Gene profiling analysis shows specific molecular signatures according to the histotype and prognosis of stage I ovarian carcinoma. The expression of a truncated form of p63 (DNp63) increases with the increased malignancy of ovarian cancer. Patients expressing high levels of DNp63 have a worst prognosis. DNp63 represents therefore a new potential target for selective therapies in this malignancy. CHK1 downregulation by specific inhibitors or sirna, increases the antitumor activity of 5- fluorouracil in vivo. This effect is particularly evident in p53 deficient tumors indicating that this combination increases the selectivity of this anticancer agent. An anthracycline derivative, Nemorubicin, has a peculiar mechanism of action and is active against tumors resistant to drugs such as cisplatin. A mechanism of resistance against this drug has been identified, which involves the abrogation of the expression of a nucleotide excision repair gene. 18