Manchester Cancer Research Centre. Progress Report November 2010

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1 Manchester Cancer Research Centre Progress Report November 2010

2 Overcoming Challenges to Drive Progress Manchester Cancer Research Centre In this report we review achievements and progress over the past year. Despite the current challenging environment faced by us and many other research institutions, we are continuing to expand our research activities through recruitment of promising and experienced staff, development of new areas of research and enhancement of existing facilities. New recruits to the Manchester Cancer Research Centre (MCRC) will increase our capabilities in tumour specific areas, such as breast and lung cancer research with a focus on the investigation of signalling networks that play a key role in the development and progression of cancer. In addition, our imaging research has been strengthened, enhancing our knowledge of and proficiency in the use of this important technology in planning and delivering treatment and monitoring patient response to therapy. We are also continuing to develop new areas of research throughout the MCRC partnership. In particular, the new Drug Discovery Centre is now well established and has initiated novel and exciting drug discovery programmes. The expertise and advice the Centre brings will be invaluable in allowing us to assess the therapeutic potential of our research and in validating prospective targets for therapeutic intervention. The creation and realisation of the Drug Discovery Centre has generated and will foster a drug-hunting culture throughout the MCRC, ensuring that our research has the end user, the patient, at the core of its strategy and promoting clinically relevant basic and translational research. Building for the future remains a key goal of the MCRC: these future developments require major capital investment in new facilities. Both short and long term projects are in progress including the Patient Treatment Centre, a 35 million facility built by The Christie NHS Foundation Trust, which is due to open ahead of schedule before the end of the year. This Centre incorporates a dedicated early phase clinical trials unit, which will be the largest such facility in the world and will boost our clinical research activities. In the longer term, plans for a new dedicated and forward-looking research facility for the MCRC partnership are well underway. The past year has been both productive and encouraging - working together in a truly collaborative manner has reaped rewards for MCRC researchers, which in the future will drive tangible benefits for patients. Professor Nic Jones Director

3 New Group Leaders Recruited Dr John Brognard, who was previously based at the Salk Institute for Biological Studies in San Diego, joined the Paterson Institute for Cancer Research as a Junior Group Leader in August His research focuses on new signalling pathways involved in tumourigenesis, the process involved in the production of new tumours. Dr Brognard s future plans are aligned with the signalling networks important in the initiation and progression of lung cancers, which will complement the Manchester Cancer Research Centre s lung cancer research initiative. Dr Pengfei Paul Lu, from the University of California San Francisco, took up a position as Group Leader in the Breakthrough Breast Cancer Research Unit, which is part of The University of Manchester s School of Cancer and Enabling Sciences. He has a background in developmental biology and is studying the function of potential tumour suppressor genes in both the epithelium and stroma of the breast. Cell-cell and cell-stroma communication and interaction play an important role in normal tissue development and aberrations in this communication process can lead to the development of cancer. Dr Lu s research focuses on understanding the roles of the stromal microenvironment in regulating adult stem cells, and on the maintenance of epithelial polarity - a key feature of organ integrity, the loss of which is often seen in breast cancer. In addition, his research explores the role and regulation of receptor tyrosine kinase (RTK) signalling in mammary gland epithelium-stroma interactions, an important signalling pathway that is often abnormally regulated in many breast cancers. Dr Lu s research will augment breast cancer research ongoing within Manchester. Professor Michael Lisanti has been recruited as Chair of Cancer Biology within the School of Cancer and Enabling Sciences at The University of Manchester; he will also be a member of the Breakthrough Breast Cancer Research Unit. Professor Lisanti is currently based at the Kimmel Cancer Center in Philadelphia and will take up the position later this year. He is a world expert in the identification and characterisation of prognostic biomarkers in breast cancer and his recruitment significantly strengthens areas of breast cancer research and biomarker research, both of which are high priorities for the MCRC. Professor Mike White, founder of the Centre for Cell Imaging in the School of Biological Sciences at Liverpool University, has recently been recruited to the Cellular Systems Division of the Faculty of Life Sciences at The University of Manchester and awarded the Chair of Systems Biology. His research focuses on understanding the dynamics and integration of cell signalling, transcription and cell fate in mammalian cells with a particular emphasis on cell division and apoptosis. Professor White will be establishing a state-of-the-art Systems Imaging Centre that will have cutting-edge technologies needed to push the boundaries of live cell imaging. Research at the new Centre will incorporate fast dynamics, which aims to measure the structure and dynamics of molecules during important biological processes, and will also incorporate single cell approaches. It is anticipated that his research team will be fully established in Manchester around spring 2011 and will undertake studies that expand the imaging research base within the MCRC, a technique that plays an increasingly important role in planning and guiding cancer treatment and monitoring patient response to therapy. 3

4 Drug Discovery Centre Where Small is Beautiful In simple terms, small molecule drug discovery programmes seek out chemicals that have the potential to become clinically useful drugs by interacting with, and altering the activity of, a target in a beneficial, reproducible and safe way. The challenge is identifying clinically relevant targets, finding small molecules that interfere with the target s activity and then optimising them so that they can be used in the treatment setting a challenge being taken up by the Drug Discovery Centre at the Paterson Institute for Cancer Research. With the aid of an 8 million 5-year funding programme from Cancer Research UK (CR-UK), the newly established Drug Discovery Centre can already list some notable achievements. Under the leadership of Dr Donald Ogilvie, the Centre has developed a clear strategy to deliver its long term objectives. A crucial first step was to provide a stateof-the-art facility able to meet existing and future needs, and a new drug discovery laboratory has been built and equipped on time and within budget, as Dr Ogilvie explained: At the start of this programme grant (April 2009), there were no suitable facilities for the Centre within the Paterson Institute but a large vacant laboratory was made available for refurbishment. Since provision of a laboratory was an obvious rate-limiting step for establishing the programme, we initiated the design phase immediately, he said. A key feature of the laboratory design is co-localisation of bioscience and chemistry activities within the same laboratory to facilitate close communication between those who design and synthesise, and those who test, compounds. The use of expert consultancy design services and the selection of equipment compatible with existing facilities delivered both cost and time savings a major consideration in the current funding climate. The laboratory was completed and handed over on schedule in December 2009 and was equipped and ready for use in just one month. Further cost savings were made through supplier negotiation and where appropriate sourcing preowned equipment, enabling the bioscience and chemistry teams to be fully operational soon after handover of the refurbished laboratory and only nine months after award of the grant. Another achievement has been the timely recruitment of a highly skilled core team enabling laboratory work to begin in January After a competitive and rigorous selection process, five medicinal/synthetic chemists (led by Head of Chemistry, Dr Allan Jordan) and four bioscientists have been appointed. Importantly all the new recruits have industrial experience, mainly in drug discovery, and the aim is to double team numbers by April 2011 when additional funding is made available. As part of the strategy for drug discovery, key partners able to deliver technology, materials and expertise, have been identified. Many of these interactions exploit the benefits of our location in Manchester. We have particularly benefited from the MCRC, which has opened many doors in The University of Manchester and our location in the Paterson Institute adjacent to The Christie NHS Foundation Trust with direct access to cutting edge basic science and clinical expertise, said Dr Ogilvie. A further benefit of the location of the Centre has been in the selection of targets for drug discovery projects. Evaluating the clinical relevance of targets is paramount and this is where our close proximity to clinical expertise at The Christie has been invaluable. We want to focus our efforts on discovering and developing drugs that will fill an unmet medical need so the clinical setting is the rational starting point, explained Dr Ogilvie. Drawing on the expertise within the MCRC, a target selection strategy has been developed and presented broadly across the MCRC leading to the identification of specific targets and priority drug discovery projects that are now underway. 4

5 Target selection is the first step in drug discovery. This is followed by identification of chemical compounds (known as hits) that interact with the target using techniques such as high throughput screening where thousands of compounds are screened simultaneously the few hundred that hit the target are then potential leads. Another method for generating hits is virtual screening based on the structure of the target, running a database search to assess which known chemicals might interact with the target. Hits are confirmed by retesting and those that combine an ability to interact with the target with the most attractive properties, such as chemical stability, are chosen for lead progression. The hits are further optimised, building a chemical with improved potency, target specificity and properties likely to make it pharmacologically active. These optimised leads are then taken into preclinical and ultimately clinical testing to assess their benefit. The researchers are using high-throughput screening and virtual screening and have now accessed capabilities in both techniques. Given the large numbers of chemicals screened and validated, drug discovery projects generate a wealth of data making optimal information management a priority. The Drug Discovery Centre has selected cutting edge informatics company Dotmatics Limited to provide a complete range of drug discovery informatics solutions, including their newly released electronic laboratory notebook system. This enables the capture, analysis and interrogation of both the biological and chemical information generated within the Centre. It also allows the scientists to make informed decisions around the best compounds to advance into further studies and ultimately into the clinic. Implementation of the informatics programme has been supported by the recruitment of a highly experienced computational chemist. What we now have available (in Manchester, and within the MCRC partnership) is the ability to identify specific unmet needs or unanswered questions that present reallife issues in the clinic. We can then undertake basic and preclinical research to identify the molecular basis of these issues and feed the molecular insight, in the form of targets, into drug discovery projects to develop leads for preclinical and then clinical testing in robust trials. With the on-site expansion of early phase clinical trials and biomarker capability, this is the ideal place to be driving successful drug discovery programmes to completion, said Dr Ogilvie. 5

6 Patient Treatment Centre Triples Space for Early Clinical Trials The new 35 million Patient Treatment Centre at The Christie NHS Foundation Trust, which is to open ahead of schedule by Christmas this year, will be home to the largest early clinical trials unit in the world and completes plans for a three-fold expansion of facilities for early phase clinical trials. With the opening of these new facilities and planned future growth in research staff, more patients will be able to have early access to new therapies. Building work began on the Patient Treatment Centre early in 2009 at The Christie s main site in Withington and the MCRC partners are eagerly awaiting the formal opening. As Professor Malcolm Ranson, Clinical Director of The Christie s Clinical Trials Unit explains: Robust clinical trials are essential in evaluating innovative treatment. The remarkable progress made in basic cancer biology is beginning to be translated into new therapies and we have focussed on delivering true bench to bedside medicine. The MCRC partners have been successful in building worldclass research teams alongside the necessary infrastructure to bring this to fruition. With this expansion in our clinical trials capacity we will be now be able to increase the number and range of trials that we can offer patients. The Patient Treatment Centre, which attracted 4.2 million funding from Cancer Research UK, also brings under one roof early phase research and service chemotherapy making the patient treatment pathway more convenient and efficient. We have tried to achieve both closer integration and a wider understanding of the importance of clinical and translational research. Having a facility designed from the outset to facilitate this has been a major achievement, added Professor Ranson. 6

7 MCRC Conference: Harnessing Apoptosis The inaugural MCRC Conference: Harnessing Apoptosis, which took place in January 2010, featured a plethora of eminent international scientists who gave insight into the basic, translational and clinical research ongoing to understand the mechanisms of controlled cell death (apoptosis), which is often aberrant in cancers. Some 120 attendees gathered in Manchester for the successful event and were treated to a wide range of talks and facilitated discussions highlighting how new knowledge in basic apoptotic mechanisms is transforming translational studies and clinical trials in cancer. The meeting opened with a plenary lecture by Doug Green, from St Jude Children s Research Hospital in Memphis, which focused on the mitochondrial pathway of apoptosis, a major route for cell death during development, homeostasis, and aging, and upon physiological or pathological stress in vertebrates. Following talks provided an overview and discussion of proteins involved in apoptotic pathways such as Inhibitor of APoptosis (IAP) proteins and BCL-2, highlighting that understanding how cancer cells overcome apoptotic signals is key to developing anticancer strategies based on overcoming cancer cell insensitivity to apoptosis. The conference also featured updates on the latest clinical developments aimed at enhancing cancer cell apoptosis and on biomarkers for early phase trials with apoptosis endpoints. In addition, alternative cell death pathways were reviewed, cell signalling pathways were evaluated and the insights gained using cancer models were discussed. The four-day conference concluded with a plenary lecture by Karen Vousden, from the Beatson Institute for Cancer Research in Glasgow, on the increasingly complex role of the tumour suppressor p53 protein in the prevention of cancer development. Harnessing Apoptosis was a great success; it showcased the high quality cancer research in this area whilst stimulating some very interesting discussion and debate. 7

8 MCRC Imaging Group: Research Motivated by Reality One year on and the MCRC Imaging Group s focus on multidisciplinary and clinically relevant research is paying dividends. The Group has taken a three-pronged approach to their research strategy with an emphasis on enhancing biomarker studies, preclinical imaging and translational imaging capability. Encouraging progress has already been made across all three strategic goals. A recurring theme within the Imaging Group is a new approach to understanding cancer and identifying appropriate targets for therapeutic intervention. We are looking at building a research strategy that has a rational focus on the hallmarks that are characteristic across tumour types. These include: proliferation, the cancer cell s ability to drive aberrant expansion; angiogenesis, the process of new blood vessel development essential for providing the nutrients that allow tumours to grow beyond a critical size; and reduction in spontaneous apoptosis, allowing the cancer to circumvent normal mechanisms of programmed cell death, explains Professor Alan Jackson, from the University s School of Cancer and Enabling Sciences, who leads the Group. This strategy means that research learnings will be reproducible and relevant to a range of cancers, allowing research insight to translate into novel approaches across different tumour types. The Oglesby Charitable Trust, a charity established in 1992 by Michael Oglesby, the Chair of the MCRC s Steering Board, recently funded a Clinical Fellowship in Translational Oncology, which has been 8

9 awarded to Dr Ioannis Trigonis. Dr Trigonis is working on developing methods to accurately measure tumour cell proliferation rates in lung, breast and pancreatic cancer. He aims to identify and validate biomarkers that can be used to provide a baseline measure of tumour cell proliferation. The research involves the use of Positron Emission Tomography (PET) imaging, which provides a valuable three-dimensional image of functional processes within the body, in combination with the biologically active molecule fluorothymidine (FLT) which is known to be an indicator of proliferative activity. Tumours are heterogeneous so different parts of the tumour exhibit different behaviours, such as resistance to therapy due to lack of oxygen (tumour hypoxia). Using FLT-PET will allow imaging of the tumour in its entirety; visualisation of these different areas can be combined with measurement of the proliferation rate of specific areas. Another clinical project, led by Professor Karl Herholz, aims to discover how inflammatory changes take place in brain tumours using PK11195 PET, a PET technique that has been applied in conditions such as stroke and Alzheimer s disease. This project is being carried out in collaboration with The Walton Centre NHS Foundation Trust in Liverpool, a specialist neuroscience centre. A major challenge in treating patients is understanding and minimising therapeutic failure. Increasingly a key clinical question is how does a tumour become resistant to therapy and how we can identify and use biomarkers to detect when resistance is likely, or when it occurs, so that therapy can be rapidly changed before the patient experiences relapse, said Professor Jackson. Another important aspect of optimising patient treatment and outcome is monitoring response to therapy. The Imaging Group aims to identify biomarkers that reflect changes in the tumour in order to inform clinical decisions about the success or progress of therapy, and to allow rational use of treatments that are tailored to patient response. The work that Dr Trigonis is undertaking will provide valuable and robust tools that can be validated and used across the Imaging Group and across a range of tumours, he added. Magnetic Resonance Imaging (MRI) using cancer models, one example being the recent successful implementation of sodium imaging. Sodium imaging has a variety of medical uses including non-invasive cartilage analysis to give an indication of joint health, cellular viability in myocardial ischemia (a lack of blood flow to the heart) and to track cell death in cerebral infarction, a type of stroke. It has also been used to differentiate tumours from surrounding tissue. One project within the group aims to use advanced MRI to develop and validate novel orthotopic models of brain tumours, models that more realistically reflect the true microenvironment that impacts tumour growth and behaviour. To support these projects, the research teams now have a new preclinical PET-CT scanner, a state-of-theart system that has now been installed and is fully functional. A translational imaging research group has been formed providing a functional basis for clinical imaging research and facilitating the translation of research findings to the clinic. The MCRC Imaging Group has a rational and cohesive research strategy which is tightly aligned with clinical need. We work to help understand the reasons for and ways of overcoming clinical issues encountered in real patients, such as resistance to therapy, by taking these questions into the preclinical setting where we can investigate their causes and identify potential solutions. These solutions can then be tested in appropriate preclinical models before entering early clinical trials and finally, if found effective and safe, entering the clinic as a new tool aimed at improving patient treatment and outcomes, concluded Professor Jackson. Manchester and for cancer patients, he said. Preclinical imaging, led by Dr Kaye Williams from the University s School of Pharmacy, is focusing on understanding metastatic behaviour and hypoxia a potent inducer of angiogenesis. The Group now have a number of active PET imaging studies underway while other joint projects have begun or are in the initiation phase. These include the development of advanced 9

10 Highlights in Radiation-Related Research Researchers involved in radiationrelated research (RRR) within the MCRC have had a year of notable success and progress and continue to deliver a coordinated and cohesive strategy. The initiative launched last year by the UK s National Cancer Research Institute (NCRI) to develop and strengthen translational RRR led to the establishment of a new Clinical and Translational Radiotherapy Research Working Group (CTRad), which aims to promote and support clinical trials that have the potential to impact clinical practice. Professor Tim Illidge, who leads RRR at the MCRC, will be taking on the role of Chair of CTRad from October 2010, while Dr Ranald Mackay, who leads North West Medical Physics at The Christie NHS Foundation Trust, is co-chair of one of CTRad s four workstreams, focusing on new technology, physics and quality assurance. Dr Mackay will be overseeing the academic professional development of physicists to optimally support improvements in RRR. Professor Ian Stratford, who leads the Experimental Oncology Group within the University s School of Pharmacy, with an emphasis on combining drugs and radiation, has been appointed as national lead within the executive group on radiation and drug combinations in cancer treatment. Professor Stratford is leading the organisation of the 22nd International LH Gray Conference Realising the potential of drug/radiation interactions in Manchester on 2-4 February The choice of Manchester as hosts of this prestigious international conference is a huge coup for the Manchester RRR and NCRI CTRad groups. The programme features a panel of international experts and will include sessions on the biological aspects of radiotherapy targets and the development of early phase trials with drug/radiation combinations. In addition, participants will be able to attend parallel workshops focusing on the optimisation of trial design with radiotherapy and novel targeted agents, and on the application of imaging in combined drug/radiotherapy trials, explained Professor Illidge. The MCRC and AstraZeneca have worked together productively through the MCRC/AZ alliance for several years and the partnership has now led to the establishment of two important RRR early phase clinical studies. The first of these is the MEK/RT trial in patients with non-small cell lung cancer (NSCLC), which has started patient recruitment. Led by Dr Corinne Faivre-Finn at The Christie, the trial aims to assess the efficacy and safety of the molecular targeted MEK inhibitor (AZD6244) in combination with radiotherapy in NSCLC patients with locally advanced or metastatic disease as radiotherapy plays a major role in the treatment of this patient subgroup. The second trial, the DREAM study focuses on rectal cancer and is evaluating two drugs developed by AstraZeneca with a novel study design; this trial is being led by MCRC clinician Dr Mark Saunders, Chair of the Gastrointestinal Tumour Study Group at The Christie. The DREAM study has a pioneering study design, which has generated considerable national interest and other centres are now using this innovative design for further studies based on the initial idea developed by Dr Saunders, explains Professor Illidge. A potentially exciting development for Manchester and the UK will be the implementation of proton therapy. The potential benefit of proton therapy over standard radiation techniques is that the pattern of radiation can be more readily conformed to the tumour itself thus allowing higher doses of radiation to be used to control and manage the cancer while minimising off-target irradiation to healthy tissue. Manchester has been selected by the Department of Health as one of only two sites nationally to submit a business case for the installation of a proton therapy facility. This exciting development was secondary to the considerable amount of ground work undertaken by The Christie and members of the RRR group led by Drs Nick Slevin, Ranald MacKay and Ed Smith. In addition, a collaboration has been established between Professor Steve Hahn's Proton Therapy Group at the University of Pennsylvania, USA, to share research findings and experience in order to optimise administration of proton therapy. The growing recognition of the strength of RRR within the MCRC partnership reflects the commitment of MCRC researchers. Professor Catharine West who leads the Translational Radiobiology Group within the University s 10

11 School of Cancer and Enabling Sciences, has established a Radiogenomics Consortium that held its first meeting in Manchester in November Following the success of this meeting, the second consortium meeting is due to be held in the USA later this year. The past year has been outstanding for Dr Faivre-Finn who along with colleagues published an important article in the Journal of Clinical Oncology entitled Improving Survival with Thoracic Radiotherapy in Patients with Small Cell Lung Cancer. The CONVERT and the REST Trials. In addition, Dr Faivre-Finn has been awarded a Clinical Excellence Award, a national Department of Health award that aims to recognise exceptional individual contributions. The number of Clinical Excellence Awards handed out nationally in 2010 has been halved, with only 317 national awards given to senior doctors in England and Wales this is a welldeserved tribute to a highly committed clinician and researcher, said Professor Illidge. 11

12 Progress in Meeting the Lung Cancer Challenge The multidisciplinary Manchester Cancer Research Centre (MCRC) Lung Cancer Research Group was set up to tackle lung cancer and provide improved treatment options for patients. Since its establishment, the Lung Cancer Research Group has made significant progress through strategic identification of priority areas to focus co-ordinated research efforts that drive enhanced patient care. The Lung Cancer Research Group includes scientists, nurses and clinicians located at The Christie NHS Foundation Trust, Paterson Institute for Cancer Research, University Hospital of South Manchester NHS Foundation Trust (UHSM), North West Lung Centre (NWLC) and The University of Manchester. The Group s research portfolio centres on the development of new therapies for treatment and has a major emphasis on discovery and application of novel biomarkers for early detection of disease and the development of personalised therapy. Two priority areas identified by the Group was the need to provide more support for early detection studies and to improve tissue acquisition for translational research. The last year has seen investment in state of the art endoscopy equipment to support ongoing and planned longitudinal studies in which populations at high risk of lung cancer will undergo surveillance to include serial biopsy of preneoplastic or neoplastic lesions. Recruitment to LUNGSEARCH, the first national trial of lung cancer screening, and a bimodality surveillance study of patients at high risk of relapse are underway, said Dr Fiona Blackhall, a lung cancer specialist at the MCRC and The Christie. In addition, the number of lung samples banked in the MCRC Biobank at UHSM now exceeds 200 and bronchoscopy specimens are also to be collected from October Tissue microarrays in squamous cell and small cell carcinoma are under construction as a resource for translational and basic scientists for novel target and biomarker evaluation. Translational research has also been strengthened with the award of a clinical lectureship to explore plasma proteomics signatures in early stage non-small cell lung cancer patients that may be relevant to future early detection of disease. Blood plasma contains a wide range of proteins some of which may be proteins that are generated during processes such as cell death. In disease processes such as cancer development, the composition or profile of the proteins carried within the plasma can be altered. By studying and defining protein profiles, the proteomics signature, in cancerous tissue, we can identify specific signatures that represent potential markers of disease, explained Dr Blackhall. The first clinical proteomics studies of serial blood samples (CHEMORES European Framework 6 funded project) from patients with advanced disease are now underway. At the Paterson Institute the lung focus group in Clinical and Experimental Pharmacology is leading the field in circulating tumour cell (CTC) detection and the application of CTCs for improved understanding of the biology of tumours. CTC s are also being evaluated to assess whether they have pharmacodynamic utility in clinical trials and if they can be used to monitor the effect of anti-cancer therapies on the body. This year the translational portfolio has extended to include radiation-related biomarkers with the award of a clinical lectureship and a clinical fellowship. Lung Cancer Research Group researchers are studying preclinical lung cancer models of novel drug/radiation combinations. The radiotherapy focus continues to grow with an emphasis on evaluating novel treatments in combination with radiation therapy. A phase I study of the MEK Inhibitor, AZD6244, in combination with thoracic radiotherapy is ongoing, while the RADAR study is assessing circulating, tissue and imaging biomarkers for prediction of radiation response and/or toxicity. The Manchester-led multinational phase III CONVERT trial, which aims to identify the optimal total 12

13 dose of radiotherapy to prescribe for small cell lung cancer and the most effective way of giving radiotherapy (comparing delivery once versus twice daily), is also ongoing. In addition, the phase II CONCEPT trial, which is investigating concurrent chemo-radiotherapy followed by consolidation chemotherapy in patients with stage II and III non-small cell lung cancer, will soon close having reached its target accrual. In terms of clinical trials, this year Manchester has risen to be the top recruiting network for National Cancer Research Network trials due to the combined efforts of the team. Through international collaboration the Group has made major contributions in phase II and III trials of second generation epidermal growth factor receptor inhibitors and ALK inhibitors. Gefitinib became the first licensed treatment for lung cancer where evidence of EGFR gene mutation is mandatory for prescription, said Dr Blackhall. We are now leading a Europe-wide initiative in external quality assurance for EGFR mutation analysis through collaboration with colleagues at the National Genetics Reference Laboratory, St Marys Hospital and several other international groups. Research towards enhancing patient treatment also includes identification of methods to improve supportive and palliative care. A new initiative that brings together expertise from established research programmes at The University of Manchester and UHSM has resulted in award of an NIHR PhD studentship for a clinical fellow and is focusing on the measurement and management of cough in patients with lung cancer. We set out clear objectives for the Lung Cancer Research Group and have made encouraging progress in key areas early detection, tissue banking, translational research, radiotherapy research and clinical trials, and supportive and palliative care. These achievements demonstrate the strength of collaboration and teamwork in delivering tangible results and the value of a partnership approach to research that is at the core of the Lung Cancer Research Group s and the MCRC s strategy, said Dr Blackhall. 13

14 Term Starts for MRes Oncology Students This September saw the first intake of MRes students into the MCRC via a new programme that provides postgraduate-level training and equips medical students with the specialist knowledge and research skills to pursue a research career in oncology. The MRes in Oncology has been designed as a practical programme with a focus on clinically relevant skills as Professor Catharine West, Postgraduate Director at The University of Manchester s School of Cancer and Enabling Sciences explains: Our aim is to stimulate the best medical students to become interested in oncology. We want to fire their enthusiasm for cancer research in order to generate a critical mass of high-quality clinical, medical and surgical oncologists who will drive progress in future cancer research. The one-year full time course accepted applications from undergraduate medical students who had completed year 4 of their degree. The MRes course combines opportunities to hone practical laboratory skills together with tutorials and lectures. Our MRes students will be getting the most up to date information on cancer, its progress and latest treatments - a real benefit is that lectures and tutorials are delivered by internationally renowned researchers and clinicians drawing on the expertise that exists across the MCRC partnership to provide an exceptional learning opportunity, said Professor West. The students also gain 35 weeks of practical experience through two research placements during the year-long course. Around 20 diverse projects have been offered and students are able to choose one which best matches their interests and may also approach other potential supervisors within the MCRC if they have a particular area of research they wish to explore. This year s intake of four students will grow as the course matures to a maximum of students per year in order to maintain a high calibre of participants. The MCRC MRes in Oncology aims to be flexible so that students can tailor relevant elements of the course to suit their individual interests. It provides students the skills and academic training that will help develop academic oncology leaders of the future, Professor West concluded. 14

15 MCRC Biobank Continues to Develop and Expand The MCRC Biobank, a regional facility that stores biological samples for research use and is located at the Paterson Institute for Cancer Research, was established in March 2008 and is proving a valuable resource for the research community it supports. In the past 12 months the repository of biological material has more than doubled and currently provides secure storage for over 1,300 patient samples, with around 60 new samples being added every month. These figures indicate that the process for collection from the five NHS Trusts involved in the Biobank collaboration is efficient and effective. So far, the Biobank has received 24 applications for sample provision to be used in academic research, 17 of which have been approved. When applications are received they undergo a peer-review process by three scientists or clinicians, including at least one expert in the applicant s proposed field of research. Each reviewer gives the project application a score; these scores are then totalled and passed on to the Biobank s Access Subgroup, which is composed of members of the Management Board. The Subgroup reviews the scores and provides final adjudication based on scientific quality. They also ensure that those involved in the logistics of sample provision are adequately consulted so that the Biobank can be sure it is able to deliver the quality and quantity of material required within the proposed timescales, explains Professor Noel Clarke, Director of the MCRC Biobank. The legal and ethical implications of the research proposal are also considered and assessed for compliance. Experience with research projects over the year have demonstrated that the Biobank is a flexible resource able to respond to changes in project needs as the research progresses. So far, the majority of sample requests have been for sections from blocks as well as blood and bone marrow samples, although recently frozen tissue has also been released. Pathology projects to mine the pathology archive are also about to start. This will expand the tissue repository and will link tissue samples to patient databases whose clinical outcomes have been documented over time, which will be a particularly valuable resource. To facilitate this there is now an expanded team of seven technicians collecting samples, including two specialists. One is a lung specialist technician funded by AstraZeneca through the MCRC/AZ Alliance and is based at Wythenshawe Hospital, part of University Hospital of South Manchester NHS Foundation Trust, and the other is a specialist in male cancers funded by the Men Matter charity and is based at Salford Royal NHS Foundation Trust and The Christie. To enable better information and access for users to the system, the Laboratory Information Management System (LIMS) database was purchased and installed six months ago. This is now up and running, with sample data being routinely logged on the system. Following this test phase the LIM System will be further customised by an in-house informatics analyst to ensure it services the needs of the Biobank. The next step is to provide secure remote access to LIMS so that technicians based at the collecting Trusts are able to enter and retrieve information from their own hospital. This should make the process simpler and more efficient, helping the Biobank provide a professional service to the research community, said Professor Clarke. 15

16 Spring Marked Launch of Breast Cancer Research Unit The Breakthrough Breast Cancer Research Unit was officially launched on 4 March 2010 and has already developed a coherent research strategy for the Unit focusing not on cancer cells themselves but on the cells and material which surround the tumour cells. Professor Tony Howell, Director of the Breakthrough Unit explains the rationale behind the strategy: Most breast cancers originate from previously normal breast epithelial cells but in normal breast tissue, epithelial cells account for only around 10% of all the cells that make up the breast. The remaining 90% is stroma - an elaborate mixture that includes blood vessels, fat cells, immune cells and a range of connective tissue cells. There is increasing evidence that although not innately cancerous, stromal cells play a pivotal role in the development and progression of cancer. By taking this relatively novel approach, Breakthrough researchers aim to answer several key questions in breast cancer. Firstly, whether it is possible to identify stromal factors that predict risk of breast cancer and therefore to focus preventative measures to high-risk groups. Secondly, whether stromal factors can be used to predict the likelihood of cancer spread or metastases and also sensitivity to treatment. Four Team Leaders have now been appointed to the Unit to drive the overarching research strategy: molecular pathologist Professor Goran Landberg, cancer cell biologist Professor Michael Lisanti, developmental biologist Dr Paul Lu, and stem cell biologist Dr Robert Clarke. Clinical associates Professor Howell, Professor Nigel Bundred and Dr Sacha Howell, provide clinical leadership for the strategy. the mechanisms of stroma-cancer cell interactions, to search for stromal markers of risk and to test the utility and validity of these markers in clinical studies. Other data within the Unit indicate that the stroma is intimately involved in the progression from localised disease to invasive disease and that the stroma indicates metastasis and resistance to treatment. This will be further explored within the Unit by focusing on the identification of stromal markers during tumour evolution, metastases and development of resistance and also by undertaking studies to better understand the mechanisms of action that underpin these processes. A final question we want to answer is whether the use of therapies directed at stromal elements, rather than the conventional target of the tumour cell itself, could improve patient response to treatment and outcome. It may be that we can identify stromal targets able to reverse resistance to standard therapy and thereby provide a more effective combination approach. However, it may be that stromal targeted therapy has the potential to become the main therapy option and not an add-on at this stage we don t have the answers. By working together in a considered and rational approach to key challenges we are ideally placed to have an impact on outcomes for breast cancer patients, said Professor Howell. The potential relationship between stromal factors and risk of breast cancer is being explored and already data from Professor Landberg s team suggest that the presence of cross-linked collagen in normal breast is associated with a higher risk of breast cancer development. Based on these and other supportive data the next steps are to elucidate 16

17 MCRC Gains Centre Status The Manchester Cancer Research Centre (MCRC) was officially accredited as a Cancer Research UK (CR-UK) Centre in April 2010, one of around 20 Centres to be accredited by the end of Manchester, which includes the Paterson Institute for Cancer Research which is core-funded by CR-UK), the NHS (The Christie NHS Foundation Trust) and the charitable sector (CR-UK), the success of the MCRC since its establishment in January 2006, provides tangible proof of the benefits that can be achieved through partnership and that are the driving force behind CR-UK s Centres initiative. The accreditation is further and formal endorsement of the collaborative strategy for research that is at the heart of the MCRC s approach to optimising the use of scientists, clinicians, facilities and resource in order to drive innovative and clinically-relevant research in cancer. The Centres initiative is a major part of CR-UK s five-year research strategy and one of its highest priority strategic programmes, the aim of which is to develop long-term, sustainable Centres of excellence in cancer, delivering worldclass research, improved patient care and greater local engagement. It was modelled on the partnership working in Manchester within the MCRC and aims to promote close collaboration between organisations that have a shared goal of improving treatments for cancer patients. As a partnership between academia (The University of 17

18 STRAT Fellowship Success The MCRC s first fellowship funded through the Singaporean Strategic Attachment and Training (STRAT) scheme ended this summer and was judged a resounding success. Dr Ying- Kiat Zee, from the National University Cancer Institute Singapore (NCIS), has recently completed a one-year placement as a clinical research fellow working with Professors Gordon Jayson and Caroline Dive; a placement that was mutually beneficial. Professor Jayson explained: Dr Zee proved himself a superb clinician and researcher. He was highly motivated to make the most of his placement and worked extremely hard throughout the year. Dr Zee focused on early clinical trials of novel anti-angiogenic agents that aim to exert an anticancer effect by targeting angiogenesis, the formation of new blood vessels upon which tumours rely for growth. As well as participating in phase I clinical trials, Dr Zee gained valuable imaging experience and made a very positive contribution to the research team. He wrote reviews for Nature and an ethics paper and continues to be involved with the Translational Angiogenesis research group within the University s School of Cancer and Enabling Sciences. Dr Zee is currently working with us in a joint project analysing metabolomics data, characterising the small molecule metabolites generated as a result of anti-cancer treatment, and has set up two clinical trials with the MCRC and another in Singapore, said Professor Jayson. One of the two collaborative trials focuses on the development and validation of assays to identify mutations in circulating DNA and the other on characterisation of circulating endothelial cells, the cells which form the inner lining of tumour blood vessels, in patients undergoing different chemotherapy treatments. The aim of these studies is to see if we can identify biomarkers that reflect damage to tumour blood vessels. Once validated, these biomarkers can be used to test the activity of future anti-angiogenic agents, explained Professor Jayson. The STRAT placement has been a real benefit to our group and also to Dr Zee and could lead to a lasting research relationship between the MCRC and Dr Zee s team. 18

19 Building for the Future Fulfilling the long-term strategy of the Manchester Cancer Research Centre (MCRC) will require an increase in research activity and capability, together with increased investment in new areas of research and continued recruitment. In particular, there is a growing emphasis on personalised medicine where treatments are selected based on improved knowledge of a patient s disease characteristics. We are almost at full capacity with existing research space and in order for the MCRC to reach its full potential, we need to provide a state-of-the-art environment where research can flourish, said MCRC Director, Professor Nic Jones. will focus on the planning and design element of the build taking into account end-user needs to ensure that the new building has the space and facilities to support high quality research. The new laboratories will be used to expand current cancer research activities, develop new strategic initiatives and continue to develop excellent research infrastructure. The development will ensure that we have a facility able to support the progress and growth that underpins future achievements, said Professor Jones. Following discussion and agreement with MCRC partners, a significant investment of 20 million has been secured for the development of a new laboratory research building. Cancer Research UK is providing 10 million towards the new build with an additional 10 million from The University of Manchester and land being provided by The Christie NHS Foundation Trust. With funding now in place, the next year 19

20 Manchester Cancer Research Centre The University of Manchester Wilmslow Road Manchester M20 4BX tel: fax: