The cell death regulator FLIP: evaluation of novel inhibitors in colorectal cancer

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Colorectal cancer is the 2nd leading cause of cancer-related death in the Western World, and the global health burden caused by this disease is forecast to increase as the populations of Western society continue to age. Thus, improved approaches to treat this disease are urgently needed. Moreover, it is important that new therapies are personalised; this means targeting them to patients most likely to benefit. This is not only important for patients, but also for struggling healthcare systems, as personalising cancer medicine means that they are spared the financial costs of ineffective therapies that may only produce toxic side-effects that require additional, costly patient care.Recently, we have found that significant subgroups of colorectal cancer patients benefit little if at all from current treatment strategies. These subgroups are readily identifiable using modern techniques which can identify the gene mutations that cause the cancer and the extent to which the body's own defence mechanisms (the immune system) are alert to the presence of the cancer. In this proposal, we aim to identify better ways of treating these patient subgroups using a new type of drug that targets a particular mechanism used by cancer cells to survive chemotherapy. Our preliminary evidence suggests that using this type of drug in combination with established chemotherapies will improve the survival rates of colorectal cancer patients in those patients, who do not benefit from current treatment by:1. Enhancing the efficacy of standard chemotherapy agents.2. Reactivating the immune system to attack the cancer. The project will use clinically relevant experimental approaches and state-of-the-art techniques to understand the molecular mechanisms by which the new drugs work to kill cancer cells and reactivate the body's immune system.The overall goal is to test these new treatments in patients. In this regard, we are fortunate to have Prof Richard Wilson as one of our key collaborators. Richard is a Clinical Academic with enormous experience in early phase clinical trials, particularly in colorectal cancer. Through Richard's engagement in this project and his role in a number of national and international colorectal cancer clinical trials networks, we will be able to rapidly translate the most promising findings from the lab into trials in patients.In summary, this project will lay the foundations for new clinical trials aimed at improving the survival of colorectal cancer patients. In addition, these results could also have implications for improving the treatment of a number of other cancers which are caused by the same gene mutations that cause colorectal cancer; these include pancreatic cancer and certain forms of lung cancer.