Cancer Therapy: Clinical A Phase 0 Trial of Riluzole in Patients with Resectable Stage III and IV Melanoma

Purpose: Ectopic expression of GRM1 in murine melanocytes results in transformation into a form of melanoma, and more than 60% of human melanoma samples tested ectopically express GRM1. Stimulation of this receptor in vitro results in up-regulation of activated extracellular signal–regulated kinase (ERK). Furthermore, a xenograft model of melanoma treated with riluzole, an oral GRM1 blocking agent, showed decreased tumor growth compared with the untreated controls. We have now completed a phase 0 trial of riluzole in patients with melanoma. Experimental Design: Patients enrolled on this trial underwent a pretreatment biopsy, took 200 mg of oral riluzole per day for 14 days, and then underwent resection of their remaining tumor. We compared the levels of pERK and pAKT in the pretreatment and post-treatment samples and assessed the metabolic activity of pretreatment and posttreatment tumors using fluorodeoxyglucose positron emission tomography (FDG-PET) scanning. Results: We accrued 12 patients and all expressed GRM1. We found a significant decrease in pAKT and/or pERK in post-treatment tumor samples as compared with pretreatment samples in 4 (34%) patients. These four patients had a significant decrease in FDG-PET intensity post-treatment as well. Two other patients had a clinical response with no corresponding metabolic response; five patients had similar pretreatment and post-treatment FDG-PET scan findings; and one patient had progressive disease. Conclusions: Our data show that glutamate blockade with riluzole can inhibit signaling through the mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT pathways and suppress the metabolic activity of melanoma. 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. Recently, our group described a heretofore unknown component of melanoma pathogenesis. A transgenic murine model of melanoma was developed by the ectopic expression of metabotropic glutamate receptor 1 (GRM1) in melanocytes (1–3). These mice spontaneously develop melanocytic lesions indistinguishable from human melanoma. We have expanded these original studies and have now shown that more than 60% of human melanomas express GRM1 and that activation of this receptor results in activation of the mitogen-activated protein kinase (MAPK) pathway in a B-Raf– and N-Ras– independent fashion (1). In preclinical studies, we have shown that the ectopic expression of GRM1 in melanocytes is transforming and that inhibition of GRM1 signaling in vitro and in vivo results in cell cycle arrest and subsequent apoptosis in human melanoma (2). We have now translated our findings into the clinic and have completed a phase 0 trial of riluzole in patients with stage III and IV melanoma. Riluzole (2-amino-6-trifluoromethoxybenzothiazole) is a noncompetitive GRM1 receptor antagonist that has been shown to be safe and effective in patients with amylotropic lateral sclerosis (ALS; refs. 4–7). Riluzole is the only Food and Drug Administration–appoved GRM1 blocking agent and is used to slow the progression of disease in patients with ALS. We now report that administration of oral riluzole resulted in suppression of MAPK pathway Authors' Affiliations: Division of Surgical Oncology, Department of Surgery, Section of Nuclear Medicine, Department of Radiology, Department of Biometrics, and Division of Medical Oncology, Department of Medicine, UMDNJ-Robert Wood Johnson Medical School; Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; and The Cancer Institute of New Jersey, New Brunswick, New Jersey Received 12/22/08; revised 2/25/09; accepted 2/27/09; published OnlineFirst 5/19/09. Grant support: National Cancer Institute grant 1 R21 CA126148-01 (J.S. Goydos). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: James S. Goydos, The Melanoma and Soft Tissue Oncology Program, The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901. Phone: 732-235-7563; Fax: 732-235-8098; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-08-3303 3896 Clin Cancer Res 2009;15(11) June 1, 2009 www.aacrjournals.org Research. on July 15, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from signaling and involution of tumor in 34% of patients. We also found suppression of signaling through the phosphatidylinositol 3-kinase (PI3K)/AKT pathway and an increase in the number of apoptotic cells in some post-treatment tumor samples. These results lead us to hypothesize that oral riluzole, alone or in combination with other compounds, may be an effective therapy for patients with melanoma. Materials and Methods We performed an Institutional Review Board–approved phase 0 trial of oral riluzole in patients with resectable stage III or IV melanoma, who were to undergo resection of their tumors. We chose a phase 0 trial design because only a few patients need to be exposed to the drug to determine if riluzole is capable of modulating GRM1 signaling in patient tumors. In addition, phase 0 trial designs have been recommended by the Food and Drug Administration as proof-of-mechanism studies for agents that modulate signaling pathways. Furthermore, because 200 mg daily seems to be the maximum tolerated daily dose of riluzole in humans (8), a dose-finding phase I trial in cancer patients was not necessary to proceed with a phase 0 trial although we will incorporate dose escalation into future therapeutic trials. The primary objective of this trial was to determine whether treatment with riluzole alters the levels of activated extracellular signal–regulated kinase (ERK) and AKT in biopsy specimens obtained before and after treatment. Sample size calculations based on examination of previous tumor biopsy specimens indicated that by enrolling 15 patients, we should have been able to detect a 25% decrease in the ratio of activated to total protein after riluzole treatment. Riluzole. Riluzole (2-amino-6-trifluoromethoxybenzothiazole) is a noncompetitive GRM1 receptor antagonist that has been shown to be safe and effective in patients with ALS (4–7). Riluzole is the only Food and Drug Administration–appoved GRM1 blocking agent and is used to slow the progression of disease in patients with ALS. Riluzole is a moderately potent noncompetitive GRM1 antagonist but is a very potent inhibitor of glutamate release by GRM1-expressing cells. How blockade of GRM1 results in slowing of the progression of ALS is unknown, but inhibition of signaling through GRM1 on binding of riluzole has been documented in neuronal cells. It has recently been suggested that riluzole is an inhibitor of protein kinase C, a central component of GRM1