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, we have now shown that expression of Grm1 in a benign melanocyte cell line results in transformation of this line and inhibition of Grm1 expression in these cells results in reversal of transformation. We have also shown that melanoma cells that express Grm1 undergo G2 cell cycle arrest and subsequent apoptosis upon Grm1 inhibition. The ectopic expression of metabotropic glutamate receptors may thus 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 will first determine if blocking Grm1 in cell lines alters their invasiveness and ability to migrate and invade tissues, their expression of the proteolytic enzyme uPA, and their ability to form vascular networks in 3D collagen culture (vasculogenic mimicry). Next, we will treat the ectopic Grm1 mouse model of melanoma, a xenograph murine model of melanoma, and a syngeneic murine model of melanoma with commercially available glutamate-blocking agents to determine whether blocking this receptor affects tumor growth in animal models of melanoma. Finally, we will see if a correlation exists between the level of production of Grm1 in primary human melanoma tumors and bad prognostic signs in human melanoma. This series of experiments should yield data that will validate Grm1 as a therapeutic target in patients with melanoma and begin to explain how Grm1 affects pathways that are important in melanoma pathogenesis. Grm receptor blocking agents are already commonly used by Neuroscientists to study and treat common neurologic problems such as epilepsy, chronic pain, and dementia. These receptor-blocking agents could quickly be adapted for use in cancer treatment protocols and the data from this proposal will help us develop clinical trials using Grm1 blocking agents in patients with melanoma. We will be using mice in this study that spontaneous develop melanoma and murine melanoma xenographs.

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National Cancer Institute (NCI)
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Developmental Therapeutics Study Section (DT)
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Ogunbiyi, Peter
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University of Medicine & Dentistry of NJ
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Mairhofer, David G; Ortner, Daniela; Tripp, Christoph H et al. (2015) Impaired gp100-Specific CD8(+) T-Cell Responses in the Presence of Myeloid-Derived Suppressor Cells in a Spontaneous Mouse Melanoma Model. J Invest Dermatol 135:2785-2793
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
Teh, Jessica L F; Shah, Raj; Shin, Seung-Shick et al. (2014) Metabotropic glutamate receptor 1 mediates melanocyte transformation via transactivation of insulin-like growth factor 1 receptor. Pigment Cell Melanoma Res 27:621-9
Wall, Brian A; Wangari-Talbot, Janet; Shin, Seung S et al. (2014) Disruption of GRM1-mediated signalling using riluzole results in DNA damage in melanoma cells. Pigment Cell Melanoma Res 27:263-74
Wangari-Talbot, Janet; Wall, Brian A; Goydos, James S et al. (2012) Functional effects of GRM1 suppression in human melanoma cells. Mol Cancer Res 10:1440-50
Khan, Atif J; Wall, Brian; Ahlawat, Stuti et al. (2011) Riluzole enhances ionizing radiation-induced cytotoxicity in human melanoma cells that ectopically express metabotropic glutamate receptor 1 in vitro and in vivo. Clin Cancer Res 17:1807-14
Lee, Hwa Jin; Wall, Brian A; Wangari-Talbot, Janet et al. (2011) Glutamatergic pathway targeting in melanoma: single-agent and combinatorial therapies. Clin Cancer Res 17:7080-92
Shin, Seung-Shick; Wall, Brian A; Goydos, James S et al. (2010) AKT2 is a downstream target of metabotropic glutamate receptor 1 (Grm1). Pigment Cell Melanoma Res 23:103-11
Wangari-Talbot, Janet; Goydos, James; Chen, Suzie (2010) Role of the G Protein-Coupled Receptor, mGlu1, in Melanoma Development. Pharmaceuticals (Basel) 3:2821-2837
Le, Maithao N; Chan, Joseph L-K; Rosenberg, Stephen A et al. (2010) The glutamate release inhibitor Riluzole decreases migration, invasion, and proliferation of melanoma cells. J Invest Dermatol 130:2240-9

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