UMDNJ-ROBERT WOOD JOHNSON MEDICAL SCHOOL
A transgenic murine model of melanoma was developed by the ectopic expression of metabotropic glutamate receptor 1 (murine GRM1 or mGRM1) in melanocytes. We have expanded these original studies and have now shown that over 65% of human melanomas express the human form of this receptor, hGRM1, and that activation of this receptor results in activation of the MAPK and PI3K/AKT pathways in a B-RAF and N-RAS-independent fashion. In pre-clinical studies we have shown that the ectopic expression of mGRM1 in murine melanocytes is transforming and that inhibition of hGRM1 signaling in vitro and in vivo results in cell cycle arrest and subsequent apoptosis in human melanoma. We have now translated our findings into the clinic and have completed a Phase 0 trial of Riluzole, an inhibitor of glutamate signaling, in patients with stage III and IV melanoma. We found that administration of oral Riluzole resulted in suppression of MAPK and PI3K/AKT pathway signaling and involution of tumor in 34% of patients. We have now embarked on a R21-funded Phase II Trial of single agent Riluzole in patients with advanced melanoma. The Parent R01 award for which we were awarded this Administrative Supplement has as its main goal the validation of hGRM1 as a therapeutic target in melanoma. One aspect of this validation is the examination of the effects of hGRM1-blockade using in vitro and in vivo models of human melanoma. Dr. Seung Shick Shin has several years of experience working in the field of cell transformation and regulation of gene expression. He has many years of experience working with animals and has assisted with the development of the experiments in Specific Aim 2 of the parent R01. He is familiar with the xenograft models we are using and he has been an invaluable asset in the laboratory, working with Dr. Brian Wall and Ms Janet Talbot, the two investigators funded by the Parent R01 to perform the xenograft work. Dr. Shin was supported by different funding sources that came to an end and Dr. Shin needed to be laid off from his position in the laboratory of Dr. Chen. The loss of Dr. Shin would have been a serious blow to our ability to complete the work on Specific Aim 2 in a timely fashion. We sought funds from the ARRA program to keep Dr. Shin working in our Laboratory. Since joining our laboratory team Dr. Shin has continued his work and we have completed 2 Aims of the parent grant with excellent data that will help us design the next phase of our translation of our findings into clinical trials for patients with advanced melanoma.