2014 Grants

Professor Dean Harris, Swansea University – PhD studentship

Project Title: Raman spectroscopy and colorectal cancer: towards early diagnosis and personalised medicine

Amount: £99,604

Duration: 36 months

Colorectal (bowel) cancer remains a leading cause of cancer-related death in the Western World. This research will investigate if bowel cancer can be diagnosed by a simple blood test. Early diagnosis before symptoms develop, such as rectal bleeding or change in bowel habits, is vital for the best outcome. Current screening tests, such as colonoscopy or faecal blood detection kits, can be invasive, unpleasant and expensive, so alternative tests are needed. At the Centre for NanoHealth (CNH) in Swansea we will use a technique called Raman spectroscopy to detect cancer- related changes in patient samples. This technique measures the scatter of laser light caused by cells, chemicals and molecules to create a unique ‘fingerprint’ that is predicted to be specific for colorectal cancer. Such approaches will help make screening for colorectal cancer more acceptable and accessible. In future, the technique may also help determine which types of chemotherapy will work for a particular patient, and cancer recurrence could be detected earlier, transforming outcomes for this common cancer.

Dr Andrew Godkin, Cardiff University – PhD studentship

Project Title: Evaluating how autoreactive T cells promote progression of colon cancer

Amount: £99,144

Duration: 36 months

The immune system can recognise colorectal cancer (CRC) cells. In particular, T cells (also known as T-lymphocytes, a type of white blood cell) may control the growth and spread of cancer. Some T cells appear to recognise tumour cells exclusively i.e. they do not recognise any other cell in the body (tumour-specific T cells) whereas others recognise both tumour cells and normal cells (self or autoreactive T cells). It is widely thought that both types of T cells participate in the control of cancer growth. We recently followed up 58 patients treated by surgery for CRC. The presence pre-operatively of autoreactive T cells, recognising a protein expressed on both normal tissue and cancer cells, was associated with early cancer progression and patient death. This is both a surprising and extremely important result, as it may enable us in the future to identify high-risk patients and treat more effectively.

Dr Zaruhi Poghosyan, Cardiff University – PhD studentship

Project Title: ADAM15/PTK6 interplay: promoters of prostate cancer progression

Amount: £100,476

Duration: 36 months

We have identified that an enzyme, called ADAM15, which can cut and release growth factors from the outside of prostate cancer cells, can cause cancer cells to spread. We have shown that more aggressive cancers produce a form of ADAM15 that has increased scissor/cutting activity and can release growth factors more efficiently from the tumour cells. This suggests that the production of distinct ADAM15 forms can identify aggressive prostate tumours that have high risk of spreading to bone and other organs and can be used to help distinguish aggressive cancers from non-metastatic cancers. We will use prostate cancer patient samples from the Wales Cancer Bank to screen for the presence of ADAM15 forms in tumour tissue and correlate the presence of the distinct ADAM15 forms with diagnosis and the severity of disease outcome. We have shown that the “aggressive” ADAM15 forms bind to a signalling protein, called PTK6, in cancer cells. We think that this binding allows prostate cancer cells to grow out of control and spread to distant organs. We will test whether blocking ADAM15 binding to PTK6 can stop prostate cancer cells from growing and moving to distant sites.

Dr Jane Wakeman, Bangor University – Post-doctoral fellowship

Project Title: Understanding and delineating the cancer associated functions of Brachyury

Amount: £138,605

Duration: 30 months

Cancer cells arise from normal cells in the body when key ‘tumour driver’ molecules are expressed at the wrong time. Identifying key ‘tumour drivers’ and how they work to change the normal cell into a cancer cell is of critical importance to our understanding of this disease and how to treat it effectively in the long term. We (and others) have shown that when a molecule known as Brachyury is present in a cell it allows the cell to adopt cancer associated properties. Furthermore, we have recently shown that having Brachyury in the cell allows the cell to divide but when the levels are reduced the cell stops dividing and adopts a ‘resting-like’ (quiescent) state. In this state, the cancer cells can possibly evade tumour destroying drugs that work on dividing cells. This project will identify the molecular mechanisms that enable Brachyury to work in colorectal cancer cells and separate this function from possible roles it has in normal cells. This information will provide a platform to help develop effective targeted therapies to colorectal cancer and may also help in defining the disease stage (which is important factor in choosing an appropriate treatment).

Professor Mark Gumbleton, Cardiff University – PhD studentship (The Cancer Research Wales, Ed Evans Fellowship for Brain Cancer Research)

Project Title: Caveolin-1 and glioma tumour initiator cells

Amount: £114,896

Duration: 36 months

Gliomas are the most common form of brain tumour and display an ability to invade neighbouring healthy tissue and to resist drug and radiation treatments. Surgical resection inevitably leaves some remaining tumour tissue at the edge of the cavity which is able to re-establish itself often in a more aggressive form.  There is increasing evidence indicating that within solid tumours there exists a subpopulation of cancer-initiating cells or cancer stem cells (CSCs) which impart tumour characteristics associated with aggressive disease and poor prognosis. The features of advanced glioma suggest that this tumour type possesses enhanced CSC-like characteristics.  We believe that a protein, caveolin, is a key determinant of CSC-like properties in glioma and represents a novel target for future CSC-directed therapy. In this project, we will interrogate the functional properties of caveolin with respect to stem-like characteristics in cancer cells and patient samples, where the latter have clinical parallels to progressive disease. The findings of this work will have significance for the understanding of biomarkers of cancer stem-cell in glioma and characterising the most functionally aggressive glioma stem-cell populations. Ultimately the work should impact upon disease prognosis and more specific targeted therapies.

Dr Andrew Sanders and Professor Wen Jiang, Cardiff University – PhD studentship (Partnership Grant)

Project Title: Functional role of Epithelial Protein Lost In Neoplasm (EPLIN) in prostate cancer metastasis

Amount: £47,897 (50% of total costs)

Duration: 36 months

Prostate cancer is one of the most commonly diagnosed male cancers and a leading cause of male cancer deaths in the UK. Progression of the disease can vary greatly from the cancer undertaking an indolent course, where the patient will die with prostate cancer rather than of prostate cancer, to a very aggressive course where the cancer will progress quickly and spread away from the primary site. Prostate cancer has a tendency to spread to the bones and this is associated with poor patient outcomes.  The main research goal of this project is to explore mechanisms that may aid this spread to and cancer cell colonisation of the bones, and to determine if there are any therapeutic potential in targeting such mechanisms. The current project will investigate a molecule called Epithelial Protein Lost In Neoplasm (EPLIN) and its importance in the spread of prostate cancer cells to bone.

Dr Ned Powell, Cardiff University – PhD studentship

Project Title: DNA repair and radio-sensitivity in human papillomavirus-associated oropharyngeal cancer: therapeutic potential

Amount: £90,992

Duration: 36 months

Around 500 patients are diagnosed with Head and Neck (H&N) cancer every year in Wales, and cancers arising in the tonsils and tongue base (‘oropharyngeal cancers’) have doubled in incidence over the last ten years. This increase is caused by infection with Human Papillomavirus (HPV), a very common virus, which also causes cervical cancers. HPV associated oropharyngeal cancers affect younger (<60 yrs), mostly male patients and show different clinical behavior to HPV negative cancers. There is an urgent need to improve understanding of the molecular biology of HPV driven tumours to facilitate better treatments.  There is good evidence that HPV infection changes the way cells repair damage to their DNA. HPV infection appears to cause defects in repair of DNA breaks caused by radiotherapy and some types of chemotherapy. These defects may make HPV driven tumours more vulnerable to chemo/radiotherapy than normal cells. The aim of this project is to exploit this defect in DNA repair to make tumour cells even more sensitive to therapy than normal cells. This can potentially be achieved by “synthetic lethal” approaches. This approach depends on inhibiting the remaining functional DNA repair pathways in HPV-positive cells. In normal cells, this effect will be tolerated and the cells will survive, but in tumour cells, the loss of multiple DNA repair pathways should result in higher levels of DNA damage that cause greater cancer cell death.

Dr Andrew Westwell, Cardiff University – Post-doctoral fellowship

Project Title: Inhibitors of αB-crystallin (CRYAB) for the treatment of triple-negative breast cancer

Amount: £115, 380

Duration: 24 months

Breast cancer is a complex disease made up of a number of sub-types that dictate disease progression and patient survival. Significant advances have been made in recent years in disease classification, underlying tumour biology and successful treatment. However one particular sub-type of disease, the so-called triple negative type of breast cancer, remains particularly problematic. Triple-negative breast cancer (approximately 15% of all breast cancers) is often found in younger women with early metastasis (spread) to vital organs, conferring aggressive early relapse and worse overall survival. Previous studies by the project co-applicant (Dr. Jun Cai) have identified a protein known as αB-crystallin (CRYAB) that is present at high frequency in triple-negative breast cancer. In pilot studies, specific disruption of the interaction between CRYAB and another important angiogenesis protein known as VEGF has been shown to sensitise cancer cells to chemotherapeutic drugs and decrease tumour aggressiveness. In this project we will build on this powerful “proof-of-concept” through the computer-aided design, chemical synthesis and human breast cancer cell testing of new molecules targeting CRYAB-VEGF. The primary goal of this research is the discovery of a new therapeutic approach towards triple-negative breast cancer, which can be further developed towards clinical evaluation.

Dr Tracey Martin and Professor Wen Jiang, Cardiff University – PhD studentship (Partnership Grant)

Project Title: HAVcR-1 and the prevention of metastatic disease in human prostate cancer

Amount: £47,347 (50% of total costs)

Duration: 36 months

Understanding how prostate cancer spreads is fundamental to identifying ways to treat patients with the disease. This work will aim to provide an insight into how this process occurs and will identify a possible target for therapy. Although treatment and diagnosis of prostate cancer has had extraordinary advances in recent years, the underlying mechanisms of how this cancer spreads and how we can prevent this from happening is still ongoing. We hope to provide evidence of how prostate cancer can spread, identify a target for therapy and hopefully develop a potential inhibitor to this target. This project aims to determine how cancer cells escape and spread around the body and how we can prevent this from occurring. We will look at how a particular protein that is increased in prostate cancer is able to promote the spread of prostate cancer. We will also look at specific potential inhibitors that can prevent this from happening. Ultimately, this study could result in a test that can contribute to predicting which prostate cancer patients will have a more aggressive disease, and could also lead to a therapy against the spread of prostate cancer.

Dr Girish Patel, Cardiff University – PhD studentship

Project Title: Elucidation of the role of transforming growth factor beta signalling in cancer stem cell drug resistance

Amount: £95, 979

Duration: 36 months

Many cancers have mutations that alter key growth promoting pathways, keeping them permanently “switched on” to drive cancer cell division. Over the last decade, drugs have been introduced that can simultaneously inhibit a number of these different pathways. While malignancies in patients often demonstrate an initial response to these drugs, cancer recurrence is frequently observed. My group over the last five years has defined cancer stem cells (CaSC) in the two commonest skin cancers, using internationally agreed assays. We have shown in high impact scientific publications that basal cell carcinoma (BCC) CaSC are resistant to both conventional chemotherapy and the recently approved growth factor inhibitor vismodegib. Microarray analysis of treated and untreated BCC CaSC reveals a novel role for the transforming growth factor beta pathway in mediating this resistance. In this proposal we plan to substantiate these findings experimentally and ask if blocking transforming growth factor beta signalling alone or in combination with vismodegib could result in CaSC killing, potentially offering a new treatment option for certain types of skin cancer.

Dr Steve Man, Cardiff University – Post-doctoral fellowship

Project Title: The function and clinical significance of CD4+ T cell subsets in chronic lymphocytic leukaemia.

Amount: £44,504

Duration: 12 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 make 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. There are many different types of T cell. One important group are CD4 T cells, which control many aspects of the immune response. The importance of these T cells is shown by HIV infection, which kills CD4 T cells and leads to immune suppression. We have discovered that the CD4 T cells in CLL patients are different in many aspects from those in age-matched healthy individuals. In particular, they seem to have the characteristics of “exhausted” cells that have lost their activity and function. This project will investigate CD4 T cells from CLL patients in detail, testing whether they are activated or “exhausted”. We aim to find markers related to these CD4 T cells, that will help us to predict which patients have weak immune systems and which patients will respond best to treatment.

Dr Alan Parker, Cardiff University – PhD studentship (Partnership Grant)

Project Title: Incorporation of αvβ6 targeting peptide into novel, low seroprevalance adenoviruses and their evaluation as vectors for cancer virotherapy applications

Amount: £50,738 (50% of total costs)

Duration: 36 months

Drug resistance represents a major problem for conventional cancer treatments. To overcome this, many researchers are focussing on developing “tamed” forms of viruses to treat cancer by genetically mutating them so that can they replicate and kill only cancer cells.  This is commonly known as “virotherapy”, and the viruses utilised, “oncolytics”.  Amongst the oncolytic viruses best studied is a type are a class of viruses known as adenoviruses that causes mild infections of the respiratory tract.  Of the 57 different types of adenoviruses that have been discovered to date, only one, Ad5, has been studied in detail for its ability to treat cancer.  Whilst Ad5 shows potential, its use as an oncolytic is limited by the significant proportion of individuals who have been exposed to the virus previously (ranging from 40-95% of the population, depending on ethnicity), and whose immune system recognises and clears the virus following administration. Furthermore, the Ad5 receptor, CAR, is not expressed on the majority of tumours. This proposal will therefore seek to develop new types of “designer” adenoviruses that are infect cells using a receptor called αvβ6 which is present on the vast majority of cancer cells, but not expressed on normal, non-malignant cells.