S Pugh - MRC - MR/M018423/1 - The role of miR-31 in regulating response of colorectal cancer to EGFR inhibition

Bowel cancer is the second most common cause of cancer death in the UK. Death usually results from spread to other parts of the body, of which the liver is the commonest site. Approximately one quarter of patients with bowel cancer that has spread to the liver are able to have an operation to remove the cancer. Of those the majority are treated with chemotherapy as well to try and reduce the likelihood of the cancer coming back. Over the last decade there has been interest in the use of targeted cancer therapies including cetuximab which is a growth factor blocker. This treatment is currently recommended by NICE for people with bowel cancer that has spread to the liver that is not suitable for surgery, at an estimated additional cost of £17,000 per patient. The New EPOC trial was undertaken to see if people with operable bowel cancer that has spread to the liver would also benefit from this treatment. The study treated patients with routine chemotherapy before and after liver surgery with or without cetuximab. The aim was to see whether the addition of this treatment would reduce the chance of the cancer getting worse or coming back after the operation. Unfortunately the trial produced an unexpected result such that patient's cancer came back sooner in the group receiving cetuximab. It is imperative that we conduct further research in order to understand why this happened. At the time of agreeing to participate in the trial, patients were also asked to give consent for their tissue to be used for studies in the future. These include redundant formalin fixed samples of their original bowel cancer and samples from their liver operation. This tissue now forms a vital resource for us to conduct laboratory based studies to try and explain this trial result. MicroRNAs are a recently discovered form of genetic material. They are expressed in healthy tissue, but corrupted in cancer. Our preliminary data shows that the level of a particular micro RNA, miR-31, expressed by the bowel cancers of patients in the New EPOC study may correlate with how they responded to treatment with cetuximab. The aim of my project is to study the mechanism behind this observation, that is the role of miR-31 in the response of a bowel cancer to the growth factor inhibitor cetuximab. Our preliminary work certainly suggests that it is likely to play an important role, but at present we do not know exactly which genes it is controlling. We will explore the mechanism by which miR-31 influences the progression of bowel cancer using tried and tested laboratory techniques which enable us to quantify cancer invasion and metastasis development. We will also use a mouse model to replicate the treatments used in the New EPOC study in order to dissect whether it was a particular combination of treatments, e.g. liver surgery combined with the growth factor inhibitor, that was detrimental. This project has key implications for the treatment of patients with bowel cancer in the future. The current restriction of the use of cetuximab to patients without a genetic change in their tumours called a KRAS mutation has proven insufficient in a number of studies, including New EPOC, to predict benefit. Determining the functional role of miR-31 in regulating the response of bowel cancer to growth factor blockers would enhance our understanding of which patients would benefit from these treatments, and assist in rationally selecting patients for use of targeted drugs. This, together with validation of miR-31 as a predictor of response in other trials, may permit the development of a test to allow better patient selection in the future thereby sparing those that will not likely benefit from the associated toxicities and loss of opportunity to receive other treatments. In the longer term it may open up new therapeutic opportunities for bowel cancer, and given the substantial costs of this targeted therapy provide health economic advantages also.