Abstract LB-244: A phase 0 trial of riluzole in patients with resectable stage III or IV melanoma.

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Abstract Recently, our group described a murine model of melanoma that is based on ectopic expression of metabotropic glutamate receptor 1 (Grm1). Grm1 is a normally occurring receptor in the central nervous system of mammals that controls excitatory neural impulses. Ectopic expression of this receptor in melanocytes results in transformation of these cells into a murine form of melanoma indistinguishable from human melanoma. We also found that >60% of human melanoma samples tested ectopically to date express Grm1 while normal skin and melanocytes from the same patients fail to express this protein. Furthermore, stimulation of this receptor in vitro results in downstream upregulation of phosphorylated (activated) ERK, demonstrating that this receptor is involved in the regulation of the MAPK pathway, a pathway in the cell important in melanoma formation and growth. Finally, a murine xenograft model of melanoma treated with riluzole, an oral Grm1 blocking agent, showed decreased tumor growth in the treated mice compared to the untreated controls. The goal of this study was to validate Grm1 as a therapeutic target in humans with melanoma. To accomplish this we enrolled patients with resectable stage III and stage IV melanoma on a Phase 0 NCI Quick Trial of oral riluzole. We performed a pre-treatment biopsy, treated the patients with 200 mg of oral riluzole per day for 14 days, and then resected the patients’ remaining tumors. We compared the level of pERK in the pre- and post-treatment tumor samples to determine if treatment with an oral Grm1 blocking agent results in modulation of the Grm1 signaling pathway in human melanoma. We also assessed overall metabolic activity and proliferation of the tumors pre- and post-treatment, using PET scanning, assessement of pre- and post-treatment mitotic rate of the tumors, and pre- and post-treatment Ki-67 staining intensity. We have accrued 10 of the 15 patients we need for this trial and all 10 appear to express Grm1. Preliminary results demonstrate a significant decrease in pERK in post-treatment tumor samples as compared to pre-treatment samples in 50% of the cases so far (P<0.01). We also found a significant decrease in post-treatment Ki-67 staining in one patient. Three patients had a significant decrease in PET intensity post-treatment while all other patients had similar pre- and post-treatment PET scan findings except for one patient whose post-treatment PET scan revealed progressive disease. Our preliminary data demonstrates that glutamate-blockade with riluzole can inhibit signaling through the MAPK pathway and suppress metabolic activity of melanoma in a significant number of patients. The ectopic expression of metabotropic glutamate receptors may be important in the pathogenesis of human melanoma and targeting this pathway may be an effective therapy for patients with melanoma.