TPS309 Background: Our group made the novel discovery that ectopic expression of GRM1 in murine melanocytes results in transformation to melanoma (Pollock, Nat Genet. 2003). Indeed, aberrant GRM1 expression is detected in >60% of human melanoma cell lines and biopsies, and in vitro human melanoma cells respond to stimulators or inhibitors of GRM1, which modulate cell growth and signaling cascades including extracellular signal-regulated kinase (ERK). In a xenograft model of melanoma treated with riluzole, an oral agent that blocks glutamate release, tumor growth was decreased compared with controls (Namkoong, Cancer Res. 2007). To explore mechanistic and pharmacodynamic effects of riluzole in human melanomas, a phase 0 trial was performed. 12 patients with stage III/IV resectable melanoma received riluzole 200 mg qd X 14 days prior to surgery. 4 (34%) showed significant post-treatment decreases in a) tumor levels of pAKT and/or pERK and b) FDG-PET intensity (Yip, Clin Cancer Res. 2009). These data show that glutamate blockade with riluzole inhibits signaling through the MAPK and PI3K/AKT pathways and suppresses the metabolic activity of melanoma, indicating that GRM1 may be important in melanoma pathogenesis. We thus sought to explore, for the first time to our knowledge, the antitumor activity of riluzole in melanoma patients. Methods: Patients with stage III unresectable or stage IV melanoma, ECOG PS ≤ 2, and adequate organ function will be given rilzuole 200 mg qd X 6 weeks before restaging, with the primary endpoint of tumor response. Using a Simon two stage minimax design to test the response rate of 5% vs. 20% at alpha=0.05 and power=80%, 13 will accrue in stage 1. If 0 responses are seen the trial will terminate; otherwise, 14 patients will accrue (total 27). If ≤ 3 responses are noted, no further investigation as a single agent is warranted. For the secondary aim of overall survival measurement, cumulative event rate and confidence interval will be calculated by the Kaplan-Meier method. Pre/post treatment levels of pERK, pAKT, and activated caspase 3 will be compared using appropriate parametric or nonparametric methods. 6 patients have been enrolled with paired tumor samples obtained from most to date. No significant financial relationships to disclose.
'%3e%3ccircle r='20' fill='%23008'/%3e%3ccircle r='17.5' fill='%23fff'/%3e%3ccircle r='3.5' fill='%23008'/%3e%3cg id='d'%3e%3cg id='c'%3e%3cg id='b'%3e%3cg id='a' fill='%23008'%3e%3ccircle r='.875' transform='rotate(7.5 -8.75 133.5)'/%3e%3cpath d='M0 17.5.6 7 0 2l-.6 5L0 17.5z'/%3e%3c/g%3e%3cuse xlink:href='%23a' transform='rotate(15)'/%3e%3c/g%3e%3cuse xlink:href='%23b' transform='rotate(30)'/%3e%3c/g%3e%3cuse xlink:href='%23c' transform='rotate(60)'/%3e%3c/g%3e%3cuse xlink:href='%23d' transform='rotate(120)'/%3e%3cuse xlink:href='%23d' transform='rotate(-120)'/%3e%3c/g%3e%3c/svg%3e)
