Rationale: Melanoma is an aggressive disease for which there has not been an effective curative treatment until recently. The treatment of advanced melanoma has historically lagged behind that of other cancers due to the limited impact of conventional chemotherapy and the aibllity of immunotherapy to modulate the clinical course of a small percentage of patients. An increasing understanding of the somatic genetic alterations that give rise to melanoma has spawned hope that oncogene, directed therapy might prove valuable in the management of this aggressive disease. The discovery of activating BRAF mutations in 2002'*'^'provided the first tractable target for a potent and selective pharmacologic inhibitor. However, the field was stalled for years by the lack of such agents for use in clinical trials, with the first generation BRAF inhibitor, sorafenib, failing to demonstrate efficacy'^. The first generation of highly selective BRAF inhibitors, PLX4032 and GSK2118436, have now completed phase 1 and phase 2 testing and have demonstrated unprecedented short-term efficacy among patients with metastatic melanoma harboring a BRAF mutation'""""""""^. 60 to 70% of patients achieve objective responses early in the course of therapy, and approximately 90% of all patients realize some degree of tumor regression. However, evidence that single agent therapy will not produce long lasting clinical benefit in the setting of advanced disease has also manifested with the median duration of response being nine months for those who achieve an objective response early on. and the overall median progression free survival being 6 to 7 months for all patients treated. Only a small subpopulation (fewer than 10%) achieves complete responses or has responses that last for 18 months or longer. While the early efficacy results associated with either of the BRAF inhibitors compares very favorably to any other available therapy for advanced melanoma, and regulatory approval for these agents is anticipated in the near future, there is clearly a need for research into the mechanisms of resistance so that rational combination regimens can be constructed in the future. In summary, despite the game-changing results in the clinics by the selective BRAF inhibitor, resistance has become the central question in the field: what are the mechanisms driving de novo and acquired resistance? Can combination strategies be developed to minimize its emergence? Are only autonomous tumor-cell mechanisms at play or does the tumor microenvironment in BRAF mutant melanoma promote paths of """"""""lesser"""""""" resistance to escaping the inhibitor^ effect of selective BRAF inhibitor

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZCA1-SRLB-3)
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University of Texas MD Anderson Cancer Center
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