Melanoma is among the most common and deadly human cancers. It kills more than 2000 people in the UK every year but an effective cure for metastatic disease does not exist yet.
The mutation of valine to glutamic acid at position 600 (V600E) of the BRAF kinase is found in over 60% of human melanomas, establishing it as a prominent oncogene in melanoma. Since this mutation is also commonly identified in benign and dysplastic nevi, the hypothesis is that additional mutations are required to induce melanomagenesis. Thus, a first challenge in the field is to identify those genetic events cooperating with oncogenic BRAFV600E in melanoma development, and exploit novel targets for combinatorial therapies.
Furthermore, the discovery of a central role for the BRAFV600E mutation in melanoma has led to the development of BRAFV600E-specific drug inhibitors. Initial clinical trials report extremely promising tumour regressions in the majority of patients. However, all patients eventually relapse after several months of treatment as a result of acquired resistance. I postulate that the therapeutic inhibition of BRAFV600E alone allows tumour cells to acquire additional yet unknown mutations that finally induce drug resistance and cancer’s regrowth. Therefore a second challenge is to understand the genetic determinants and molecular mechanisms responsible for the drug resistance to BRAFV600E inhibitors, which currently represent the most promising treatment option for melanoma. The aim of this project is to use novel mouse models of melanoma that develop in the setting of a Sleeping Beauty insertional mutagenesis to identify (i) genes cooperating with oncogenic BRAFV600E to promote melanoma and (ii) genes accountable for the development of drug resistance against BRAFV600E inhibitors.
Overall, the expected results in understanding the mechanisms of both melanomagenesis and resistance to BRAFV600E inhibitors will provide novel opportunities to develop effective melanoma therapeutics.
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