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GRM1 is a Therapeutic Target in Melanoma

Janet Wangari-Talbot
B.S., Montclair State University 2005

Thesis Advisors: Dr. James Goydos. M.D
Dr. Suzie Chen. Ph.D

Graduate Program in Cell & Developmental Biology

Susan Lehman Cullman Laboratory for
Cancer Research, Room 256
Ernest Mario School of Pharmacy

Wednesday, March 21, 2012
2:00 p.m.


Malignant melanoma accounts for approximately 5% of skin cancer incidences but accounts for greater than 80% of skin cancer related deaths. Current treatments for melanoma have low response rates and it is crucial to identify ways of improving drug efficacy. Our group identified the ectopic expression of Metabotropic glutamate receptor 1 (GRM1), a G-Protein coupled receptor whose expression is normally localized to the central and peripheral nervous system in ~65% of melanoma biopsies and cell lines. Targeting of this receptor and its ligand, glutamate with Riluzole, a glutamate release inhibitor clinically showed moderate anti-tumor effects suggesting that this drug might be more effective when combined with other cytotoxic therapies. Melanoma has been shown to be a genetically heterogeneous disease where single agent therapies are likely to fail due to variations in genomic signatures making mutations identified in these tumors highly relevant in designing successful therapies. Another common mutation in melanoma is the BRAFV600E mutation which has been identified in ~ 65% of tumors. Therapeutic targeting of melanoma with inhibitors of BRAFV600E has produced mixed results with some inhibitors more effective than others based on their specificity. In the first part of this thesis, we set out to investigate whether co-inhibition of BRAFV600E and GRM1 mediated signaling would be effective in melanoma by combining a pan-Raf inhibitor; Sorafenib or the BRAFV600E specific inhibitor; PLX4720 with Riluzole. Our results indicate that additive and synergistic anti-tumor effects are observed in GRM1 expressing human melanoma cells harboring either mutant or wild-type BRAF respectively with the combination of Riluzole and Sorafenib while the combination with PLX4720 only showed additive anti-tumor effects in BRAFV600E melanoma cells. These effects observed with Sorafenib can be attributed to the sensitization of cells to Riluzole due to the suppressed expression of the anti-apoptotic protein MCL-1. The combination of Riluzole with Sorafenib in melanoma patients is currently being evaluated in a Phase II clinical trial. In the second part of this thesis, we investigated the role of GRM1 expression in driving melanoma cell growth by suppression of GRM1 expression using siRNA technology. Using the ecdysone inducible and tetracycline inducible gene expression systems, we demonstrated that suppressed GRM1 protein expression leads to reduced activation of the MAPK and P13/AKT signaling pathways. We also demonstrated a decrease in cell proliferation in-vitro and significant suppression of tumor growth in-vivo. These results support the notion that biological targeting of GRM1 could be effective in GRM1 positive melanoma patients.

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