Evaluation of non-invasive metabolic imaging biomarkers for novel RAF/MEK1/2-targeted anti-cancer agents

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Our increased knowledge of the precise processes that lead to cancer has revealed a key role for RAF-MEK proteins in the initiation and progression of this disease. In fact many drugs are now in development that aim to block RAF/MEK1/2 (also known as RAF/MEK1/2 inhibitors) and the recent FDA approval of the drug vemurafenib, which inhibits the BRAF member of the RAF family of proteins, for the treatment of skin cancers (also known as melanomas) with BRAF mutation provides key evidence for the effectiveness of this strategy.Treatments based on giving drugs to block RAF/MEK are now in clinical testing. As these forms of treatment are not expected to lead to immediately visible changes in tumour size, the traditional gold-standard for measuring clinical response, early indicators (or biomarkers) that the therapy is achieving its desired effects are required to help assess how the patient is responding and if necessary adjust the treatment plan. Of importance, in particular for the patient, are the biomarkers that do not require surgical intervention, i.e. non-invasive. Imaging techniques such as magnetic resonance (MR) provide a useful tool to follow the biology of tumours in a non-invasive way.This project will use non-invasive imaging approaches (mainly MR spectroscopy (MRS) and imaging (MRI)) to track a key feature of tumour biology that is known to be abnormally regulated in cancer, namely metabolism, and inform on how the cancer cells are affected by RAF/MEK1/2 inhibition and how any affects change when cancer cells become unresponsive to treatment. Studies will be performed in cancer cells and human tumours implanted in mice as well as samples from patients participating in a clinical trial of a drug that inhibits RAF/MEK1/2 proteins.Our experimental plan will include various cellular and molecular tests that will be combined with MRS and MRI measurements to provide information on the metabolic status of cells and tumours and understand how this relates to the anti cancer effects such as cell death caused by the RAF-MEK1/2 inhibitors.This research will help us relate our laboratory findings to what the RAF/MEK inhibitor drugs actually do in the patients. This information is crucial and will in the future help doctors determine whether a drug is acting as it is meant to and, crucially, when the therapy is no longer effective so other treatment options may be sought without delay.