2015 Grants

Dr Rob Jones and Ms Rachel Butler, Cardiff University and Velindre Cancer Centre – M.D. Research Studentship

Project Title: Investigation of biomarker determinants of treatment efficacy of fulvestrant and the AKT inhibitor AZD5363 in Oestrogen receptor

Amount: £150,603

Duration: 24 months

Patients with incurable breast cancer are at first often sensitive to hormone treatments such as tamoxifen and anastrozole. Unfortunately, the cancer eventually becomes resistant to such hormone treatments and a protein called AKT is thought to be important in causing this. Some breast cancer patients are being treated with a newly developed experimental drug that inhibits AKT in combination with the hormone therapy fulvestrant to see if treatment resistance can be reversed. This study seeks to collect patient blood samples that contain circulating DNA released from breast cancer cells. By looking at this DNA, Dr Rob Jones and his team hope to establish if the early detection of genetic mutations potentially associated with drug resistance and can help predict which patients will benefit from the combination therapy. The findings from this study will help to better individualise future cancer therapy.

Professor Andrew Sewell, Cardiff University – PhD studentship

Project Title: T-cell correlates of successful immunotherapy

Amount: £117,981

Duration: 36 months

Cancers contain immune cells called tumour-infiltrating lymphocytes (TILs) that have the ability to kill cancer cells. A type of therapy called immunotherapy is exploiting these TILs for end-stage metastatic melanoma by removing them from melanoma’s and expanding them in the laboratory before putting them back into patient blood. Remarkably, this process is currently resulting in a cure rate of around 35% in patients who have failed all other treatments. It is believed that this cure will be life-long in much the same way as we are protected against re-infection once our immune system has successfully cleared a virus. This project will have access to patients that have been cured using TILs via the leading European centre in Copenhagen who are pioneering this new therapy. The cells that are returned to patients are loaded with many different types of anti-tumour immune cells that can ‘seek and destroy’ the cancer cells by using special receptors on their surface. Professor Sewell aims to determine which of classes of these receptors are used by the patients that have successfully cleared their cancer. This will allow us to better understand why this remarkable therapy succeeds and then aim to replicate this success in other patients and with other cancer types.

Dr Edgar Hartsuiker and Professor Simon Reed, Bangor University – Post-doctoral position

Project Title: Genome-wide analysis of Topo I removal pathways that contribute resistance to Irinotecan in human cells

Amount: £182,608

Duration: 36 months

The majority of cancer treatments used in the clinic kill cancer cells by damaging their DNA. To improve their therapeutic efficiency, it is important to have a detailed understanding of the cellular mechanisms which help cancer cells to survive such treatments. Irinotecan is a clinically important cancer drug that kills cancer cells by permanently locking a protein called Topo I onto the DNA so that the cancer cell can no longer replicate its DNA and grow. Irinotecan is used to treat a variety of cancers such as those of the bowel, lung and ovary. For a cancer cell to survive treatment with Irinotecan, it needs to remove the protein from the DNA. The aim of this study is determine the exact mechanisms by which cancer cells that have become resistant to Irinotecan, remove the drug from its DNA. The results from this research will lead to an improvement of cancer therapy by guiding the choice of Irinotecan to the treatment of tumours which are predicted to be most sensitive to this drug.

Professor Alan Clarke, Cardiff University – Post-doctoral position

Project Title: Exploring tumour–stromal interactions to identify novel clinical predictors for recurrence and prognosis of colorectal cancer

Amount: £150,000

Duration: 24 months

In 2013, bowel cancer or colorectal cancer was reported to be the most commonly-diagnosed cancer in Wales and second most common cause of cancer death in the UK, with a 10-year survival rate of around 50%. One mechanism thought to underpin failed therapy is the existence of a subset of ‘driver’ cells which have been termed ‘cancer stem cells’. These cells are thought to be responsible for treatment failure, and also the recurrence and spread of bowel cancer to other distant organs.  Recent reports have shown that cancer stem cells depend on receiving messages from their neighbouring non-cancerous cells within their local environment, known as the tumour stroma. The aim of this research is to determine which biochemical messages derived from the local environment can influence the cancer stem cell population in tumours and so alter bowel cancer formation and growth. The results from this study will shed light on the basic mechanisms of bowel cancer development and will also help identify molecular signatures or “fingerprints” that will serve to further improve the clinical predictors of prognosis in bowel cancer.

Dr Emiliano Spezi and Dr Nick Patterson, Cardiff University and Velindre Cancer Centre – PhD studentship

Project Title: Advanced 3D personalised dosimetry for a clinical trial in peptide receptor radionuclide therapy

Amount: £80,341

Duration: 36 months

Molecular radiotherapy, or Molecular Radionuclide Therapy (MRT) is a successful type of radiotherapy that uses unsealed radioactive sources to treat cancer. This type of therapy is based on the delivery of radiation to malignant tissue through the interaction of an agent that can bind with molecular sites and/or receptors on the surface of cancer cells. MRT has been used for decades in the treatment of both benign and malignant diseases, however, unlike other forms of radiotherapy, methods to accurately determine the dose of radiotherapy delivered to tumour sites are less advanced. There is a recognised need to raise the standard to which MRT treatments are planned and delivered to make these forms of treatment even more successful. There is also the need to build scientific evidence to show associations between the delivered therapeutic dose and patient outcome through carefully planned clinical trials. The goal of this project is to address this gap in knowledge and practice through the development and the application of advanced tools to better individualise radiation dosing in the context of a clinical trial with radionuclide therapy for the treatment of neuro-endocrine tumours.

Dr Andrew Tee and Professor Rachel Errington, Cardiff University – Post-doctoral position

Project Title: Novel therapies that selectively kill mammalian target of rapamycin (mTOR)-addicted cancer cells

Amount: £116,201

Duration: 24 months

Growth rates of cancer cells are greatly accelerated resulting in tumour growth and cancer progression. Dr Andy Tee in collaboration with Professor Rachel Errington have recently discovered that a clinically approved drug called nelfinavir selectively killed tumour cell lines that display certain increased growth characteristics, while importantly sparing normal healthy cells. This project seeks to treat kidney and breast cancer cells with nelfinavir in combination with other clinically approved drugs to further enhance the efficiency of treatment to specifically kill cancer cells of these tumour types. Nelfinavir holds great promise as an anti-cancer drug, yet it is unclear how this drug works. This work will determine exactly how nelfinavir works in combination with other clinically approved drugs to specifically kill cancer cells, which in future will allow clinicians to fine-tune drug therapy to further enhance its effectiveness to kill cancer cells while minimising side effects.

Professor Gareth Jenkins, Swansea University – PhD studentship

Project Title: Validation of a new blood test which can detect internal epithelial cancers

Amount: £94,200

Duration: 36 months

Professor Jenkins and his research team have developed an exciting new blood test to detect cancer in patients which has the potential to represent a “game changing” event in how future cancers are diagnosed. This blood based diagnostic tool can be readily deployed to screen at-risk patients and even the general public before cancer symptoms appear. The test has been developed using oesophageal cancer as an example where it is shown to distinguish patients with a pre-cancerous condition of the oesophagus from those with cancer itself. The test detects mutations (changes) in blood cell surface proteins that are associated with the development of oesophageal cancer. It is also likely to be able to detect other types of cancer and the aim of this current project is to further validate this test before proposing its clinical use as a screening tool for cancer. There are several methodological aspects that require further development and it is hoped that the test can be adapted to detect a wider range of cancers from just oesophageal to other gastrointestinal malignancies such as cancers of the stomach, pancreas, liver and bowel.

Professor Arwyn Jones, Cardiff University – Post-doctoral position

Project Title: Inducing HER2 endocytosis and downregulation via enhanced antibody-receptor clustering as a therapeutic strategy in breast cancer

Amount: £101,124

Duration: 18 months

Breast cancer is the most commonly diagnosed cancer in the UK with approximately 50,000 new cases reported every year.  Like all cancers it arises when the processes governing normal cell behaviour are disrupted. One key mechanism by which breast cancer cells are dysregulated is the ways in they communicate with their environment.  Central to this communication are receptors or molecules sitting on the surface of cancer cells that relay messages from the outside surroundings to the cell interior.  Approximately 20% of breast cancers have an excess of HER2, a receptor that sends strong instructions for cells to grow and divide. In patients HER2 has been targeted by the therapeutic antibody Herceptin®, but success has been limited because of resistance.  Our work aims to enhance the efficacy of Herceptin by modifying the antibody in ways that we have shown to stimulate breast cancer cells to destroy HER2 receptors. We aim to identify the exact mechanisms by which HER2 receptors are degraded by cancer cells with the view to generate new Herceptin-based antibodies that induce greater HER2 degradation whilst at the same time act as shuttles for increasing the delivering of anti-cancer drugs directly to breast cancer cells.