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TPS2640 Background: AKT is a frequently hyperactivated oncogenic kinase in human cancers (Degenhardt 2006). Inhibition of AKT activates autophagy, promoting tumor survival, and hence AKT inhibitors...

TPS3112 Background: Metabotropic glutamate receptor 1 (GRM1) has been identified as a potential therapeutic target in melanoma. Over 60% of human melanomas express this cell surface glutamate receptor and excitation of GRM1 results in the activation of MAPK and PI3K/AKT pathways. Riluzole, an oral GRM1 blocking agent, results in growth arrest of melanoma cells in vitro and in vivo. We previously reported that administration of riluzole to melanoma patients suppressed activity of the PI3K/AKT and MAPK pathways in paired tumor samples (Yip Clin Cancer Res 2009). In preclinical studies, the efficacy of riluzole was attenuated in melanoma cells harboring BRAFV600E mutations, but sorafenib, a RAF kinase inhibitor, enhanced the effect of riluzole on these cells. The combination of riluzole and sorafenib was additive or synergistic in both BRAF mutant and BRAF wildtype melanoma cells in vitro and in BRAF wildtype cells in a xenograft model (Lee HJ Clin Cancer Res 2011). We thus designed a phase I trial to test the combination of riluzole with sorafenib in patients with solid tumors and advanced melanoma. Methods: The primary objective of this trial is identification of the maximum tolerated dose (MTD). An expansion cohort at the MTD is planned for patients with advanced melanoma to examine the correlation of clinical or radiographic response with signaling through the MAPK and PI3K/AKT pathways and with GRM1 receptor status of individual tumors. Eligible patients must have advanced solid tumors (phase I) or stage III unresectable/stage IV melanoma with biopsiable tumor (expansion cohort) and ECOG PS ≤ 2. Riluzole will be administered at 100 mg twice daily combined with sorafenib beginning at 200 mg daily and escalating in subsequent cohorts at 200 mg increments. Correlative studies: Tumors will be assessed for BRAF and NRAS mutational status. Pretreatment tumor blocks will be examined for GRM1 receptor status by immunohistochemistry. Pre and post treatment levels of pERK and pAKT will be measured in paired tumor samples to assess effects of treatment on MAPK and PI3K signaling. Limited sampling pharmacokinetic studies will be performed. Progress: Accrual to three cohorts is complete without DLT. Accrual to the final planned cohort is in progress.