2012 Grants

Dr Emiliano Spezi, Velindre Cancer Centre – PhD studentship

Project Title: MOZART-Parameters affecting tumour control and toxicity in oesophageal cancer: a multi-dimensional outcome analysis

Amount: £67,235

Duration: 36 months

The initial step in radiotherapy (RT) for all cancers relies on clinicians outlining the tumour and normal tissues. Within national RT trials there are multiple investigators from different centres and it is important to ensure inter-observer consistency. SCOPE 1 is a Velindre-sponsored NCRI trial of chemo-radiation (CRT) in oesophageal cancer. The accuracy of outlining in SCOPE 1 has been addressed by asking all potential investigators to outline volumes for the same patient (‘test case’) which were compared to an ‘expert’ volume. We found substantial variation in tumour outlining between investigators. We found under-outlining where some of the tumour is missed and over-outlining where additional normal tissue is included. Under-outlining can lead to lower tumour control rates and over-outlining to increased toxicity although very little work has been conducted into quantifying this. The aim of this research is to determine how variations in outlining might impact on clinical outcomes (tumour control and toxicity) through the detailed analysis of the SCOPE 1 test case data and the development of innovative metrics and computerised data exploration tools. We aim to correlate this with clinical outcome of patients within the trial and develop optimal protocols for future oesophageal radiotherapy trials.

Professor Andrew Westwell, Cardiff University – PhD studentship

Project Title: T-cell receptors for immunotherapy

Amount: £86,235

Duration: 36 months

Traditional approaches to cancer therapy such as radio- and chemotherapy have numerous side effects. There is increasing interest in using the body’s own immune system to fight cancer. One of the main immune weapons in this approach are immune cells called killer T-cells. Killer T-cells can directly recognise and destroy cancer cells via a molecule on their surface called a T-cell receptor (TCR). Here we aim to use new approaches for identifying novel anti-cancer TCRs. First, we will screen existing banks of millions of T-cells in order to identify those that possess good anti-cancer TCRs. Second, we will use novel techniques to isolate TCRs from cancer patients. Effective TCRs can be genetically engineered into a patient’s own T-cells. These cells can then be put back into the patient’s blood to provide a powerful ‘natural’ anti-cancer therapy that can last a lifetime and has minimal side effects. We have also recently used TCRs as soluble molecules (drugs) to cure cancer. Our goal is to will identify effective new anti-cancer TCRs and to apply these to ongoing immunotherapy approaches to combat cancer.

Dr Ned Powell, Cardiff University – Post-doctoral fellowship

Project Title: DNA methylation as a triage test to augment HPV testing in cervical screening

Amount: £75,679

Duration: 18 months

In Europe, cervical cancer is the second most common cancer in women aged between 15 and 44 years. Infection with Human papillomavirus (HPV) is the underlying cause of cervical cancer. However, infection with HPV is very common and in most cases causes no harm. In the near future, testing for HPV infection will replace the methods currently used in cervical screening to prevent cancer. This presents a problem however as many, especially young, women will present with transient (harmless) infections. To avoid causing unnecessary anxiety in women with positive HPV test results, there is an urgent need for methods to distinguish between infections that will progress to cancer, and those that will not. DNA methylation is a chemical modification of DNA, which the body uses to regulate how genes are turned on and off. We have strong preliminary evidence that the pattern of DNA methylation is different in HPV infections that will lead to cancer and those that will not. The aim of this project is to use the methods we have established, to investigate DNA methylation in cervical screening samples with known clinical outcomes. This will allow us to determine if this test will be useful in conjunction with HPV based cervical screening.

Dr Richard Clarkson, Cardiff University – PhD studentship

Project Title: Design and synthesis of molecular inhibitors of cFLIP activity as a therapeutic strategy to target breast cancer stem cells

Amount: £104,662

Duration: 36 months

We have recently shown that suppression of cFLIP allows the anti-cancer drug TRAIL to selectively destroy the small minority of cells within a breast tumour that are responsible for new tumour growth.  This novel effect has potentially significant implications for the prevention of tumour spread to other organs.  What is now needed is an efficient method of suppressing cFLIP in patients so that this novel approach could be tested in the clinic. The aim of this project is to generate a chemical inhibitor of cFLIP that ultimately could be used as a cancer drug. First, we will perform a detailed study of the cFLIP molecule, determining how it is regulated and where it is distributed within breast cancer cells. Second, we will use this information to identify areas on the surface of the cFLIP protein that we could bind small chemicals to interfere with its function.  This will involve computer assisted modelling, drug design and subsequently, synthesis of the chemical compounds.  State-of-the-art molecular assays will be used to validate the effect of these compounds on cFLIP activity within cells, as a first step towards developing a novel therapeutic agent for breast and possibly other cancers.

Dr Steve Man, Cardiff University – PhD studentship

Project Title: The role of CD8 T cells in poor prognosis leukaemia

Amount: £100,720

Duration: 36 months

Chronic lymphocytic leukaemia (CLL) is the most common type of leukaemia in the UK. The disease is caused by changes in white blood cells called B cells that makes them cancerous. CLL patients also have problems with other types of white blood cells called T cells. These are a vital part of the immune system, and protect the body against infection. We found that around 47% of patients have large numbers of a particular type of T cell. Our early work suggests that there is relationship between patients with large numbers of T cells and disease progression. In this project, T cells from patients will be studied in fine detail using new technology. We will still study blood samples from untreated and treated (chemotherapy) patients. We want to discover why some patients have large numbers of these T cells. We aim to find markers on the T cells that will help predict which patients will respond best to treatment.

Professor Malcolm Mason, Cancer Research Wales, Chair of Clinical Oncology

Project Title: Molecular characterisation of the Wales Cancer Bank collection: all Wales initiative

Amount: £1,500,000

Duration: 60 months

Many patients with cancer are treated satisfactorily with surgery, radiotherapy with sometimes the addition of chemotherapy.  The focus of cancer research now concentrates on those patients who need more tailored treatment using drugs that target particular pathways that make cancers more aggressive.  However, using these new drugs as single agents has been disappointing, suggesting that we do not fully understand the role that these targets play in cancer development.  Cancer is a diverse disease and targeting of treatment in the future is likely to require an understanding of how the various molecular targets we have identified work together or against each other. These patients would possibly benefit from drugs aimed at these novel targets, once they have been identified. This study aims to identify the proportions of breast, urological, gynaecological, lung and head and neck tumours in the WCB that have been collected from patients across Wales and have common targets for the new cancer drugs, and to identify the small, but significant number where we still have new targets to identify.  We will also link the presence of these drug targets with clinical presentation and outcome. This will help us to identify in the future which patients can be treated appropriately with conventional cancer therapy and which should be selected for tailored treatment, using more expensive diagnostic tests and treatment regimens.

Dr Jane Wakeman, Bangor University – PhD studentship

Project Title: The role of TEX19 in growth and maintenance of colorectal cancer stem cells

Amount: £91,605

Duration: 36 months

We have collaborated in a ‘directed’ search for a specific group of genes which we rationalised would be present in cancer cells but not in normal cells (except for the testis). As such, these genes have great potential as diagnostic markers and also as therapeutic targets. Using this directed approach we isolated a number of candidate genes, one of which is a gene known as TEX19. This was originally identified in the mouse as being associated with the testis, and also specific expression has been shown in a type of cell present only early on in development, known as embryonic stem cells. Recent studies in our lab have shown that TEX19 is not expressed in normal tissues (except in the testis, as predicted), but it is expressed in a wide range of tumour types. Preliminary work in our lab also suggests that TEX19 is ‘marking’ a sub-group of cancer cells known as cancer stem cells, which are thought to be important in maintaining growth of the tumour and may be the cells that are responsible for relapse and resistance to therapies. We will study the role of TEX19 in maintaining cancer stem cells in colorectal cancer.

Dr John Staffurth, Velindre Cancer Centre – MD clinical fellowship

Project Title: Adaptive image-guided radiotherapy strategies for bladder and cervical cancer to enable dose escalation and reduce late toxicity

Amount: £67,235

Duration: 24 months

Radiotherapy in the pelvic region offers cure in several tumour sites, including bladder and cervix cancer, but can lead to long term side effects in a significant proportion of patients. To help improve outcomes, we would like to be more accurate, avoid more normal structures and treat with higher doses. There are several advances in radiotherapy occurring at the moment that offer these, but we need to improve our understanding of the complexity of pelvic radiotherapy to achieve optimal benefit. The volume of normal tissues irradiated to critical doses is associated with late side effects for most anatomical regions; in the pelvis the key structure is the bowel. However, there is a lack of detailed knowledge of safe limits for bowel irradiation and we will study this. The structures in the pelvis (bowel, bladder, rectum and uterus) move, which is a major hurdle to overcome for accurate radiotherapy delivery, given daily over 4 to 6 weeks. Advances in the imaging facilities on our treating linear accelerators offer us the opportunity to repeatedly image during treatment and improve treatment delivery accuracy. We will study the images collected during treatment to define optimal future treatment strategies for patients with bladder and cervix cancer.

Professor Richard Neal, Bangor University – Project Grant

Project Title: Root causes of diagnosis and treatment delay: International Cancer Benchmarking Partnership (ICBP) Module 4 for Wales

Amount: £114,858

Duration: 18 months

Early detection of cancer is crucial for favourable patient outcomes, the earlier a cancer is diagnosed the easier it becomes to treat, manage and cure. Early diagnosis of cancer has become a priority area for the healthcare system, particularly in Wales, where it is fair to say that late presentation of malignancy in people is an acute concern and impacts upon survivorship. With the hypothesis that differences between countries in cancer survival may be partly rooted in differences in time interval from first symptom until diagnosis and treatment, the overall aim of Module 4 is to collect valid international comparable data on time intervals. The specific aims of Module 4 are: (i) To quantify and compare the time interval from onset of first symptoms to start of treatment, (ii) To assess and compare the proportion of patients entering the cancer pathway through different routes: screen detected; urgent referrals with a suspicion of cancer; routine/urgent referrals but not specific for the suspicion of cancer; an elective route; emergency presentation, and other or unknown routes to diagnosis, (iii) Identify time intervals where actions to reduce delays could be focussed.