Recently, our group has described a murine model of melanoma that is based on ectopic expression of metabotropic glutamate receptor 1 (Grm1). Grm1 is a normally occurring receptor found 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 so far tested ectopically 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 MARK 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 ectopic expression of metabotropic glutamate receptors may be important in the pathogenesis of human melanoma and the goal of this proposal is to validate Grm1 as a therapeutic target in humans with melanoma. To accomplish this we propose to enroll patients with resectable stage III and stage IV melanoma on a phase 0 trial of oral Riluzole. We will perform a pre-treatment biopsy, treat the patients with 200mg of oral Riluzole per day for 14 days, and then resect the patient's remaining tumor. We will compare the level of activated phopholipase C beta and activated ERK 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 will also assess overall metabolic activity and proliferation of the tumors pre and post-treatment, using PET scanning, assessment of pre and post-treatment mitotic rate of the tumors, and pre and post-treatment Ki-67 staining intensity. We hope to show that treatment of patients with Riluzole results in modulation of the Grm1 pathway and decreases proliferation and metabolic activity in human melanoma tumors. If successful we will next conduct a phase II trial of oral Riluzole in patients with stage IV melanoma to determine if Grm1 blockade is an effective therapeutic option in patients with melanoma. ? ? ?
| Yip, Dana; Le, Maithao N; Chan, Joseph L-K et al. (2009) A phase 0 trial of riluzole in patients with resectable stage III and IV melanoma. Clin Cancer Res 15:3896-902 |
