Developing Personalised Medicine for Malignant Melanoma.

Melanoma is a potentially deadly form of skin cancer. Approximately 50% of melanomas carry mutations in the protein kinase BRAF and drugs that target BRAF, or its downstream substrate MEK can improve progression-free and overall survival in BRAF mutant melanoma patients. However, although ~5% of BRAF mutant melanoma patients do derive long-term remission with these agents, most patient responses to BRAF or MEK inhibitors are limited because about 20-40% of patients carrying a BRAF mutation do no t respond (intrinsic resistance), and after only 6-8 months of disease control, the majority of patients who do respond will relapse (acquired resistance). Thus, although these treatments provide a new paradigm of personalised medicine in melanoma, clinical resistance is a persistent problem. I am proposing to develop systems to improve the personalisation of melanoma patient treatment. We shall use next generation sequencing and mass spectrometry to define mechanisms of resistance in late-stage melanoma patients undergoing treatment with BRAF or MEK inhibitors. We shall use this knowledge to draw guidelines that will allow improved stratification of early-stage patients to improve likelihood of response and allow prediction of likely mechanisms of resistance. Our aim is to establish processes that can be used to monitor patient responses to drugs in real time to allow clinicians to make adjustments to the treatment of individual patients as the disease evolves. In particular, we wish to use these proactive monitoring systems to ensure that patients are offered second-line treatments or clinical trials promptly once their first-line treatment fails.