Principal Investigator: James Mier, MD (BIDMC)
Co-Investigators: Michael Atkins, MD (BIDMC) and Levi Garraway, MD, PhD (DFCI)

Description
The B-RAF gene is mutated in approximately 60% of cutaneous melanomas and those with WT B-RAF frequently have mutations in N-RAS or lack endogenous raf inhibitors (e.g. RKIP, Sprouty 2), the effect of which is to ensure the activation of the MAP kinase pathway. The down modulation of B-RAF results in melanoma growth arrest. The inhibition of MEK, a dual specificity kinase immediately downstream of raf, inhibits in vitro proliferation and tumor growth - effects strongly correlated with the presence of the B-RAFV600E mutation. These data suggest that raf might be an attractive target for drug development in melanoma. Sorafenib, the first raf inhibitor to be tested clinically (and the least potent), has limited single agent activity but induces robust caspase-independent apoptosis in melanoma cell lines, largely as a result of its inhibitory effects on signaling pathways independent of raf (e.g. STAT3). The more potent raf inhibitor RAF-265 induces tumor regression in melanoma xenografts and has recently entered Phase I clinical trials. Both RAF-265 and sorafenib activate a compensatory survival pathway mediated by the kinase GSK-3β and its downstream targets JNK and p53. These signaling events limit the apoptotic effect of raf inhibitors such as sorafenib. The concurrent inhibition or down modulation of GSK-3β, JNK or p53 markedly increases the in vitro lethality of these drugs, suggesting that the clinical efficacy of RAF-265 might be enhanced by the concurrent administration of other targeted therapies that block these prosurvival signaling events. This application is designed to promote the clinical development of raf inhibitors in the treatment of melanoma. In Aim 1 of the application, we propose to identify genetic and other factors associated with the antiproliferative and apoptotic effects of these drugs. In Aim 2, we will determine if the enhancing effects of GSK-3β, JNK, or STAT3 inhibition on sorafenib-induced apoptosis in vitro can be reproduced in a xenograft model using the more potent raf inhibitor RAF-265. Finally, in Aim 3, we propose to carry out an Inter-SPORE Phase I/II trial of RAF-265 to determine its safety, pharmacokinetics, and pharmacodynamics and in the extension phase of the trial, to determine its clinical efficacy.

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