Between 40-67% of melanoma tumors contain and activating BRAF mutations (almost always V599E). Upstream of BRAF, activating mutations in N-RAS are seen in another 5-36% of melanomas. Thus, activating mutations in the MARK pathway are seen in most melanomas. These observations along with many in vitro and animal studies indicate that the MARK pathway is critical for melanoma growth. Our overall objective is to interfere with the MARK pathway in melanoma as a treatment strategy. BRAF depends on HSP90 for proper folding and there is evidence that mutated BRAF is even more dependent on HSP90. Inhibition of HSP90 by 17-AAG results in depletion of BRAF in cell lines and in xenograft models and inhibition of cell growth. Other HSP90 client proteins of interest in melanoma depleted by 17-AAG are CDK4 and AKT. Phase I studies using 17-AAG in a variety of cancer types have defined a weekly dose of 450 mg/m2 as the most promising phase II dose. Although few melanoma patients have been included in these phase I trials, some clinical responses have been reported. We propose a phase II trial of 17-AAG in patients with metastatic melanoma at a dose of 450 mg/m2/week x 6 every 8 weeks. Two cohorts of 25 patients each - one cohort with wild-type BRAF and one cohort with mutant BRAF - will be treated. The trial will be conducted at MSKCC (lead institution), Cancer Inst. of New Jersey, and H.Lee Moffitt Cancer Center.
Specific aim #1 : Determine the clinical response rate in each cohort and test the hypothesis that tumors with mutant BRAF will be more sensitive to 17-AAG.
Specific aim #2 : Test the hypothesis that treatment with 17-AAG can disrupt the MAPK pathway by depleting intra-tumor stores of BRAF and/or downstream proteins such as phospho-ERK, CDK4 and cyclin D1. To address this, we will obtain tumor biopsies in the first 10 patients pre-treatment and 18-48 hr following the first 17-AAG treatment. Tumors will be analyzed by Western blot and immunohistochemistry. A secondary aim is to determine if effects on the MAPK pathway correlate with clinical responses or with the presence of mutated BRAF in the tumor. We also intend to analyze the biopsies by expression array profiling. As an exploratory analysis, we will compare expression patterns in pre-treatment vs. post-treatment specimens, clinically responding tumors vs. non-responding tumors, and mutant BRAF vs. wild-type BRAF tumors. ? ? ?
| Solit, David B; Osman, Iman; Polsky, David et al. (2008) Phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with metastatic melanoma. Clin Cancer Res 14:8302-7 |
