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 MAPK pathway, a pathway in the cell important in melanoma formation and growth. 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. We have now begun to translate these findings into the clinic by completing a phase 0 trial of oral Riluzole in patients with resectable stage III and IV melanoma. In this trial we demonstrate that 200mg of oral Riluzole is well tolerated by most patients with little toxicity reported. We also found that 4 out of 12 patients had clinical and molecular responses to therapy as measured by PET scanning and Western Blot anaylsis. We will now conduct a phase II trial of oral Riluzole in patients with stage advanced melanoma to determine if Grm1 blockade is an effective therapeutic option in patients with melanoma by determining response rate, durability of response, and to determining long-term toxicity of this therapy.
We have discovered what appears to be an important component of the process that leads to the formation of melanoma. This component, the expression of Grm1, appears to be important in the growth and proliferation of human melanoma. We have performed basic science experiments that show that Grm1 expression by melanomas is important for growth and proliferation and we have performed animal experiments that demonstrate that an oral medication, Riluzole that targets Grm1 signaling in melanoma cells, can stop the growth of human melanomas. We have also now performed a preliminary trial in humans with melanoma (a Phase 0 trial) that demonstrates that oral Riluzole can positively affect melanoma tumors in patients with melanoma. We now want to perform a Phase II trial that will examine whether oral Riluzole can cause shrinkage of melanoma tumors in patients with advanced disease, whether this shrinkage is long lasting, and what the toxic side effects of long-term administration of Riluzole are. This is the first time Riluzole has been used to treat cancer and a Phase II trial is the first step in proving that this therapy is effective in patients with melanoma.
| Shin, Seung-Shick; Jeong, Byeong-Seon; Wall, Brian A et al. (2018) Participation of xCT in melanoma cell proliferation in vitro and tumorigenesis in vivo. Oncogenesis 7:86 |
| Mehnert, Janice M; Silk, Ann W; Lee, J H et al. (2018) A phase II trial of riluzole, an antagonist of metabotropic glutamate receptor 1 (GRM1) signaling, in patients with advanced melanoma. Pigment Cell Melanoma Res 31:534-540 |
| Wen, Yu; Li, Jiadong; Koo, Jasmine et al. (2014) Activation of the glutamate receptor GRM1 enhances angiogenic signaling to drive melanoma progression. Cancer Res 74:2499-509 |
