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1 Changing Lives BLF Research 2011/12 helpline: e: w:

2 Contents Introduction Head of Research Ian Jarrold Editor Allie Anderson Design Sarah Chivers British Lung Foundation Introduction Completed grants 05 Development of a questionnaire to measure quality of life for people with pulmonary fibrosis 06 Preventing lung damage in COPD 07 Investigating a new drug target in mesothelioma Awarded grants 08 Asbestos-related disease research funding 10 Is it feasible to use a combined package of different treatments to relieve pain in mesothelioma patients from an early stage of 11 GADD34: a potential drug target in malignant mesothelioma 12 Current asbestos exposures and resulting mesothelioma risks in the UK population 14 Overcoming resistance to drugs used to treat mesothelioma; development of a novel, effective therapeutic strategy 15 Testing the ability of a new drug to increase the effectiveness of radiotherapy in the treatment of malignant mesothelioma 16 Understanding the genetic causes of mesothelioma Clinical Research Training Fellowship Award 18 New approaches to tackling mesothelioma Red Balloon Award 20 Supported discharge for individuals with COPD: is a comprehensive self-management manual (SPACE self-management programme of activity, coping and education) effective? 23 Acknowledgements Welcome to Changing Lives BLF Research 2011/12. This booklet provides an overview of British Lung Foundation (BLF) research grants awarded between November 2010 and November 2011 and reports on the results of selected BLF-funded research projects that were completed during this time. The economic climate over the last year or so has continued to be a challenge to everyone, but we are delighted to report that with the generous help of our supporters, we have been able to grow many key areas of our work. This includes an increased spend on world-class research into new preventions, treatments and cures for lung disease. During the year, we have awarded a host of research grants focusing on asbestosrelated disease. This is part of a three-year initiative in which 1 million will be spent each year on research and awareness-raising in this important field. We have also awarded the Red Balloon grant for respiratory research in the West Midlands and a Clinical Research Training Fellowship, which was awarded in conjunction with the Mick Knighton Research Fund and the Medical Research Council (MRC). Collaborative funding is a great way for us to add value to our research spend, and we are delighted to be continuing these relationships. We have also invested more money than ever before in travel fellowship awards. Thirtytwo grants of 750 each were made during the year, helping exceptional early-career researchers to present their work at world-class research conferences in the USA and Europe. These awards were sponsored by GlaxoSmithKline and Napp Pharmaceuticals. Finally, the BLF research team presented the findings of BLF survey work at the British Thoracic Society Winter Meeting in December 2011, raising the profile of our work at an international research conference. I look forward to seeing the results of the research projects we ve awarded this year and to supporting yet more cutting-edge work in the future. I hope you enjoy reading about the progress we re making in tackling lung disease. Ian Jarrold Head of Research 02 Changing Lives BLF Research 2011/12 Changing Lives BLF Research 2011/12 03

3 Completed grants Preventing lung damage in COPD Professor Maurice Hallett Cardiff University 60,000 ( 30,000 contribution from the Medical Research Council) 36 months COPD People who have chronic obstructive pulmonary disease (COPD) experience feelings of breathlessness that seriously affects their quality of life. Research evidence suggests that COPD is linked to long-term inflammation in the lungs. During inflammation, white blood cells move from the bloodstream to the lung spaces where it is thought that they cause damage to the lung tissue. This stops the lungs from doing their job properly, causing breathlessness and other symptoms in COPD. During this grant Professor Hallett supervised PhD student Kim Lewis, who studied how white blood cells move from the bloodstream to the lungs. The aim of the work was to gain a better understanding of this process and begin to develop new ways to reduce the movement of white blood cells into the lungs, limiting the damage caused in COPD. This research found that in order to move from the bloodstream and into the lungs, white blood cells need to change shape. They flatten out so they can squeeze between cells in the wall of blood vessels and move into the lungs. The work also showed that an enzyme called calpain is critical to this shape-changing ability. When the researchers used drugs that stop calpain from working, they found that the white blood cells were no longer able to change shape and therefore could not leave the bloodstream and enter the lungs. The work was carried out in cells grown in controlled laboratory conditions and not in human participants. The next step will be to work on converting these lab results into a safe, working treatment in people. This will involve the design of safe drugs that inhibit calpain only in specific white blood cells and not in other important cells in the body. Although a good deal of work is needed to produce a new treatment for COPD, this study is a pioneering step towards this goal. Professor Hallett studied at University College London and is now based at Cardiff University. During this grant, he supervised Kim Lewis, who was studying for her PhD. Changing Lives BLF Research 2011/12 05

4 Completed grants Completed grants Janelle Yorke University of Salford 14, months Idiopathic pulmonary fibrosis Development of a questionnaire to measure quality of life for people with pulmonary fibrosis Idiopathic pulmonary fibrosis (IPF) is caused by repeated injury to small areas of the lung, which results in scarring. This scar tissue stops the lung doing the job of transferring oxygen from the air into the blood and removing carbon dioxide from the bloodstream. The result is increasing breathlessness when undertaking activities such as walking and talking. The causes of IPF and how it develops are not well understood. In addition, although treatment options are available, monitoring the progression of the condition and the success of treatment is difficult. In other diseases, questionnaires on quality of life are extremely valuable in doing this, as they focus on things that are important to the patient such as the ability to carry out the tasks of day-to-day life. Prior to this grant, no such questionnaire existed for monitoring IPF. During this study, Janelle Yorke worked with people who have IPF to create an internationally recognised questionnaire that captures information about how IPF affects a person s quality of life. This questionnaire is a great step in helping doctors to measure the progression of IPF, which in turn will help in the prescribing of appropriate treatments and in monitoring their success. As treatment decisions can now be made depending on what s important to people with IPF, the questionnaire will greatly improve quality of care for this condition. Janelle Yorke is a lecturer at the University of Salford School of Nursing. After training in Sydney, Australia, Janelle relocated to Imperial College London and then Manchester to pursue her interest in the care of people with lung disease. Investigating a new drug target in mesothelioma Dr Richard Morgan University of Surrey 30, months is a form of cancer that is almost always caused by exposure to asbestos many years previously. It occurs in the pleura the thin lining that coats and protects the lungs. There is no cure for mesothelioma and usual cancer treatments such as surgery, chemotherapy and radiotherapy have limited success. New, effective treatments are urgently needed to help tackle this disease. During this study, Dr Morgan and his team focused on the role of a group of molecules known as HOX proteins. These proteins are important in controlling how we grow and develop throughout our lives. Research studies have shown that these proteins are far more abundant in cancer cells than normal cells. Evidence suggests the proteins can promote the growth of cancer cells and help them to survive when they are exposed to anti-cancer drugs. Recently, a drug known as HXR9 has been developed that stops HOX proteins from working. Initial studies have shown that this drug can kill lung, kidney and ovarian cancer cells, but it has not been thoroughly tested in mesothelioma. During this study, Dr Morgan tested the HXR9 drug to see if it is effective in treating mesothelioma. Results confirmed that mesothelioma cells do have far higher levels of HOX proteins than healthy lung cells and that treating mesothelioma cells with the drug can indeed kill them. Reassuringly, the study also found that the drug does not kill healthy lung cells. This work was carried out in mesothelioma cells grown in the laboratory and clinical trials are now needed to test whether the drug could be a safe and effective mesothelioma treatment in humans. It might also be possible to predict who will respond well to the drug by measuring the amount of HOX protein in a sample of a patient s mesothelioma. This would help to minimise unnecessary use of the drug and any associated side-effects. As current treatments for mesothelioma are limited, this is a very exciting step forward in pioneering new individually tailored therapies for this deadly condition. Dr Morgan is a senior lecturer in cell and developmental biology at the University of Surrey. He was awarded a PhD at the University of Birmingham and has previously worked in Utrecht, the Netherlands. 06 Changing Lives BLF Research 2011/12 Changing Lives BLF Research 2011/12 07

5 Asbestos-related disease research funding Inhalation of asbestos fibres can lead to the development of lung conditions including asbestosis (scarring of lung tissue) and mesothelioma (a cancer of the lining that surrounds our lungs). Despite progress in the medical care for asbestos-related diseases, treatment remains inadequate and new strategies are urgently needed. With this in mind, the BLF is helping to tackle asbestos-related disease by investing 3 million between 2011 and Part of this will be spent on raising awareness of asbestos and the danger it poses, but the majority will be spent on research into the prevention, treatment and cure of asbestos-related disease. Allocation of the first year s research funding has now taken place. We received dozens of exciting and interesting applications that were evaluated by international experts to decide which applicants would be funded. Changing Lives BLF Research 2011/12 09

6 Asbestos-related disease research funding Asbestos-related disease research funding Is it feasible to use a combined package of different treatments to relieve pain in mesothelioma patients from an early stage of GADD34: a potential drug target in malignant mesothelioma John Edwards University of Sheffield 24, months s People who have mesothelioma experience pain from early in the course of the disease. This pain can have multiple causes such as tumour spread, tissue inflammation and damage to nerves between the ribs and around the spine. The pain can be difficult to treat but does respond to a range of pain-killing drugs. Conventional guidance from the World Health Organisation recommends starting individual pain treatments in a sequence, from the simplest to the more advanced and powerful. In addition, standard pain treatment often ignores the value of specific procedures that can block affected nerves. There is increasing research evidence to suggest that it might be better to offer more complex treatments earlier as a combination package. During this grant, John Edwards and his team aim to test the feasibility of offering mesothelioma patients a combination package of up to five pain treatments from the first time they develop mild to moderate pain. This may include specific procedures to block affected nerves, where appropriate. The team aims to assess whether this approach to treating pain in mesothelioma is more successful than conventional methods. We hope this work will lead to earlier, more rapid and more effective relief of pain with reduced side-effects for mesothelioma patients. This would make a large contribution to improving quality of life for people living with mesothelioma by minimising pain and its consequences. John Edwards qualified from the University of Birmingham and was appointed consultant thoracic surgeon in Sheffield in He trained in thoracic surgery in Birmingham, Bristol, Leicester, Nottingham and Sheffield. Dr Brian Huntly University of Cambridge 93, months There is an established link between asbestos exposure and mesothelioma, but the reason only some people who are exposed to asbestos develop the disease is poorly understood. If we can understand what happens inside lung cells when they are exposed to asbestos fibres, this might unlock crucial information to help us prevent and treat mesothelioma more successfully. GADD34 is a protein that has been linked with the growth of many types of cancer. Dr Huntly and his team have detected high levels of this protein in samples of mesothelioma tissue taken from patients but its effect on mesothelioma growth is not clear. During this grant, Dr Huntly and his team will supervise a PhD student, who will study GADD34 and confirm its effect on the development of mesothelioma. If this work can clarify exactly how this protein affects the growth of mesothelioma, it may confirm GADD34 as a new drug target. For example, if it is found to promote the growth of mesothelioma, the next step will be to design new drugs that decrease levels this protein in an effort to slow down or stop the tumour from growing. This would be an important step forward in a disease that currently has only a limited response to existing treatments. In addition, the results from this work may also prove to be applicable to other cancers, including lung cancer. Dr Huntly studied at the University of Edinburgh and the University of Cambridge. He is currently senior clinical lecturer at the Cambridge Institute for Molecular Research. 10 Changing Lives BLF Research 2011/12 Changing Lives BLF Research 2011/12 11

7 Asbestos-related disease research funding Current asbestos exposures and resulting mesothelioma risks in the UK population Julian Peto is Professor of epidemiology at the London School of Hygiene and Tropical Medicine. He has worked at the University of Edinburgh and at Sir Richard Doll s Cancer Epidemiology and Clinical Trials Unit at the University of Oxford. Professor Julian Peto London School of Hygiene and Tropical Medicine 199, months Widespread asbestos use continued in the UK until the 1980s, and it was finally banned in Due to a 30-year lag between asbestos exposure and any detectable health problems, numbers of new cases of diseases like mesothelioma are still on the rise, mainly in people who worked with asbestos before the ban. Case numbers are predicted to peak in around Despite the ban, removal of existing asbestos was not required and it is still present in many buildings constructed before The effect of asbestos exposure after the ban is therefore of great public concern. Due to the time lag, the full extent of the health effects of post-ban exposure will not be seen for several years. Moreover, as there is very little evidence regarding asbestos exposure levels since the ban, little is known about how case numbers of asbestos-related disease will change in future. During this grant, Professor Peto and his team will study large numbers of people in the UK population and collect information about asbestos exposure in the environment and due to working practices since the 1980s. The information will be used to estimate future risks of asbestosrelated diseases. This will allow the team to make reliable estimates of how the number of UK cases of asbestos-related disease is likely to change after the predicted peak in 2015 and also which current occupations represent the highest risk. There are several potential benefits of this work. Having a better idea about future levels of asbestos-related disease will help in the planning and targeting of health care provision and research into asbestosrelated disease. Establishing which sections of the population are currently most at risk of asbestos exposure will also help to maximise the effectiveness of asbestos awareness campaigns and prevent future cases of these diseases. 12 Changing Lives BLF Research 2011/12 Changing Lives BLF Research 2011/12 13

8 Asbestos-related disease research funding Asbestos-related disease research funding Overcoming resistance to drugs used to treat mesothelioma; development of a novel, effective therapeutic strategy Testing the ability of a new drug to increase the effectiveness of radiotherapy in the treatment of malignant mesothelioma Dr David Waugh Queen s University Belfast 188, months is highly resistant to many treatments, including chemotherapy, and new, more effective treatments are urgently needed. New approaches are essential to help us to understand drug resistance in mesothelioma and to find ways to overcome it. Recent evidence suggests that mesothelioma cells are protected by molecules known as IAPs (inhibitor of apoptosis proteins) and that this protection stops treatments like chemotherapy from working to its full capacity. During this study, Dr Waugh and his team will perform laboratory tests on a new class of drug called IAP inhibitors. These drugs aim to eliminate the protection provided by IAPs, which in turn should make mesothelioma cells more susceptible to treatment. In addition, the team plans to carry out work that will help doctors to predict which people will respond well to IAP inhibitors, so that they are only prescribed to people who would benefit from them. We hope that the work will demonstrate that IAP inhibitors are effective against mesothelioma cells. This proof is an essential step towards clinical trials that will test the drugs in humans. In the longer term, the results from this project could lead to a new, personalised, effective therapy and improved outcomes for people who have mesothelioma. Dr Waugh has trained and worked in both the UK and USA, where he gained a PhD in biomedical sciences. He is now based in the School of Medicine, Dentistry and Biomedical Sciences at Queen s University, Belfast. Professor Anthony Chalmers University of Glasgow 199, months Although radiotherapy is effective in the treatment of many types of cancer, it is not effective in mesothelioma. When cells are treated with radiotherapy, the damage is recognised and signals are sent that cause the cells to die. However, mesothelioma cells do not recognise these death signals, so they survive the radiotherapy treatment and the tumour continues to grow. Professor Chalmers and his team have recently found that treating cancer cells with a drug called TRAIL activates a different type of death signal, which increases the ability of radiotherapy to kill the cells. The drug does not affect noncancerous cells, so it has the potential to increase the success of radiotherapy without worsening side-effects. However, this technique has not yet been tested specifically in mesothelioma. During the course of this grant, Professor Chalmers and his team will carry out lab tests to investigate whether using this drug makes radiotherapy a more effective treatment against mesothelioma cells. The team will also perform experiments to determine if there is a way to identify which individuals are likely to respond well to the drug, so that the therapy is only used in people who would benefit. If this work is successful, it will pave the way for clinical trials that will test the therapy in people. We hope this will produce an effective new approach to treatment for mesothelioma. Professor Chalmers studied at the University of Oxford and the University of London. He is now chair of clinical oncology at the University of Glasgow. 14 Changing Lives BLF Research 2011/12 Changing Lives BLF Research 2011/12 15

9 Asbestos-related disease research funding Understanding the genetic causes of mesothelioma Our genes are the blueprint for how our cells grow, develop and function. Cancer results from changes or mutations to specific genes. In cancer, these mutations cause cells to grow in an out-of-control manner. identification of every genetic change in a given cancer sample. During this study, Dr Campbell will use this technology to identify exactly which genetic mutations are present in samples of mesothelioma taken from 50 patients. Knowing which genes are important, and what they do, will help scientists to design more effective ways to treat mesothelioma. Dr Campbell has studied in Australia, New Zealand and at the University of Cambridge. He is now a group leader in the Sanger Institute s cancer genome project and a practising haematologist at Addenbrooke s Hospital in Cambridge. Dr Peter Campbell Wellcome Trust Sanger Institute, Cambridge 145, months A single type of cancer can behave very differently in different people, and this includes how fast the cancer grows, how it spreads and how it responds to treatment. These characteristics are controlled by the specific genetic mutations that are causing the cancer. Understanding exactly which mutations are causing an individual s cancer will help explain the behaviour of that cancer and also help doctors to make informed treatment decisions. In mesothelioma, we know that the mutations are most often caused by exposure to asbestos but little is known about which genes are affected and why they are important. In the last two to three years, gene sequencing technologies have allowed the This could pioneer a new approach to treating mesothelioma, in which treatment choices are made according to the genetic makeup of an individual s cancer. This individually tailored approach would mean that drugs are given only if they are likely to be successful, thereby minimising unnecessary treatments and associated side-effects. We hope this research will move us closer to a detailed understanding of how mesothelioma develops, to new, effective therapies for the disease and to a system in which an individual is given tailored treatment for their individual cancer. 16 Changing Lives BLF Research 2011/12 Changing Lives BLF Research 2011/12 17

10 Clinical Research Training Fellowship Award New approaches to tackling mesothelioma Current treatments for mesothelioma have limited success and new approaches are urgently needed to help treat this deadly condition. One approach is to starve the tumour cells of the nutrients they need to grow. Previously, Dr Phillips and her team have shown that mesothelioma cancer cells die when they are starved of a nutrient called arginine. This nutrient is an important building block of proteins and other key molecules that are vital to the growth of mesothelioma. Previous research has suggested that an arginine-lowering drug called ADI-PEG20 may be useful in treating mesothelioma. Although arginine starvation may be a promising therapy, Dr Phillips is concerned that a type of white blood cell found within the cancer, called the macrophage, can directly feed the tumour cells with arginine. This might reduce the effectiveness of arginine-lowering drugs. In this study, Dr Phillips will investigate the macrophagemesothelioma cell relationship in the context of arginine-lowering drug treatment. In doing so, the team hopes to learn more about enhancing the success of arginine-starvation therapy. We hope this project will lead to the development of new strategies for the treatment of mesothelioma and improve outcomes for patients with this devastating disease. Dr Melissa Phillips Barts and the London School of Medicine and Dentistry 235,752 (Joint award with the Medical Research Council and a 100,000 contribution from the Mick Knighton Research Fund) 36 months Dr Phillips has studied at the University of Birmingham and King s College London. She is now a clinical research fellow at the Barts Cancer Institute in London. 18 Changing Lives BLF Research 2011/12 Changing Lives BLF Research 2011/12 19

11 Red Balloon Award Supported discharge for individuals with COPD: is a comprehensive self-management manual (SPACE self-management programme of activity, coping and education) effective? Sally Singh studied at Loughborough University and is now professor of pulmonary and cardiac rehabilitation at Coventry University. Professor Sally Singh Coventry University 74, months COPD What s the problem and who does it Chronic obstructive pulmonary disease (COPD) causes increasing breathlessness and reduced ability to carry out the physical tasks of every day life. In addition, people with COPD experience flare-ups of symptoms known as acute exacerbations. Exacerbations can be so serious that they result in admission to hospital. Evidence suggests that there is a lack of support for people who leave hospital after they have experienced a serious exacerbation of COPD. Indeed, 30 per cent of these people are likely to be readmitted to hospital with a subsequent exacerbation. New tools are needed to help support COPD patients after they leave hospital, to help them regain their previous quality of life and prevent future flare-ups. Over the last few years Professor Singh and her team have developed a written self-management manual for COPD. This is called SPACE the self-management programme of activity, coping and education. The manual is designed to help people to recognise their symptoms and regain previous fitness levels, aiming to increase quality of life and reduce the chances of future flare-ups. However, the manual is yet to be fully tested. The aim of this study is to test the SPACE manual in COPD patients when they leave hospital following a flare-up. To do this, patients will be recruited to the study when they leave hospital and will be given either the usual follow-up care or the SPACE manual. Participants will be monitored over the course of several months to see who fares best. We hope this research will lead to improvements in care for people who have COPD when they leave hospital following an exacerbation. 20 Changing Lives BLF Research 2011/12 Changing Lives BLF Research 2011/12 21

12 Acknowledgements Thank you The British Lung Foundation wishes to thank all of the individuals, Breathe Easy groups, trusts, foundations and organisations that have given their valuable support to our research projects this year. These include: Arnold Burton CT Association of British Insurers Aviva AXA Bartlett Taylor Charitable Trust Benham Charitable Settlement Burges Bequest Charity Charles and Elsie Sykes Trust Charles Littlewood Hill Trust Coutts Charitable Trust Donald Forrester Trust Eranda Foundation Everard & Mina Goodman Charitable Foundation George John & Sheila Livanos Charitable Trust Greendale Foundation Harris Charitable Trust Henry Lumley Charitable Trust Inman Charity Joseph Strong Frazer Trust Kirby Laing Foundation Lynn Foundation Medical Research Council Mick Knighton Research Fund N M Rothschild & Sons Ltd Our research investors P F Charitable Trust Robert Luff Foundation Royal & Sun Alliance Silverdell Plc Sir Samuel Scott of Yews Trust Three T Charity Zurich and a number of trusts and foundations that wish to remain anonymous. Our special thanks go to the Garfield Weston Foundation. 22 Changing Lives BLF Research 2011/12 Changing Lives BLF Research 2011/12 23

13 The British Lung Foundation One person in seven in the UK is affected by a lung disease. Whether it s mild asthma or lung cancer, the British Lung Foundation is here for every one of them. This is what we do: We support people affected by lung disease through the individual challenges they will face. Support is the focus of many of our activities, including Breathe Easy, our nationwide network of support groups. We help people to understand their condition. We do this by providing comprehensive and clear information on paper, on the web and on the telephone. And we work for positive change in lung health. We do this by campaigning, raising awareness and funding world-class research. British Lung Foundation Goswell Road London EC1V 7ER helpline: e: w: Registered charity of England and Wales - no Charity registered in Scotland - no. SC

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