BCCMA: Determinants and early detection of metastasis in melanoma for unmet needs of Veterans with mucosal melanomas affecting the head, neck, and other rare types

Overall Research Strategy: Advancements in melanoma research and treatment over the past twenty years have not significantly benefitted Veterans and other patients with rarer melanoma types. These include mucosal melanomas (MM), which affect the head, neck, and anogenital skin; and acral melanomas (AM), occurring on the palms and the soles, which have striking genetic similarities to mucosal melanomas. The distinct clinical, molecular, and genetic characteristics of MM and AM represent a barrier to the straightforward application of current melanoma targeted therapies and immunotherapies and will require a focused approach for early detection of primary and metastatic disease and effective treatment of advanced disease. Our overarching hypothesis is that understanding the development and progression of acral and mucosal melanomas from melanocyte and melanocyte stem cell (McSC) precursors, in the context of genetically and phenotypically relevant mouse melanoma models with the experimental application of rational treatment options, will advance our ability to detect and treat these tumors in Veterans before irreversible progression occurs. We propose to test this hypothesis as a collaborative project capitalizing on the individual strengths of three seasoned VA investigators who have devoted their careers to melanocyte and melanoma research. This BCCMA project will address: CMA1 (Hornyak) – the role of McSCs in AM and MM development, testing rational experimental therapeutic strategies in a relevant mouse melanoma model and validating key targets in Veteran AM and MM specimens assembled from 5 VAMCs; CMA2 (Chen) – the role of glutamatergic signaling in acral and mucosal melanoma development and pathogenesis, including the activity of EPAC in melanoma progression and metastasis in a GRM1 mouse model highly relevant to acral and mucosal melanoma ; and CMA3 (Setaluri) – the molecular and cellular roles of EPAC and GRM1 signaling in AM and MM, including signaling activity and its relationship to melanoma cell differentiation state in circulating tumor cells. The collaborative nature of the award is critical to enable multiple approaches to this problem that would not be possible within the scope of an individual award. The projects are interdependent and will leverage the collective expertise of the investigators in melanocyte and melanocyte stem cell (McSC) biology, murine models of melanoma, therapeutic resistance, analysis of circulating tumor cells, and melanoma clinical therapeutics to advance knowledge across the spectrum of AM and MM development. CMA2 (Chen): Advances in preclinical disease models have been crucial to understand human disorders and to develop efficacious therapeutics. Melanoma patient survival of advanced melanoma has improved from less than 10% to approaching 50% currently, however, these improvements have not applied to patients with rare forms of melanoma including AM and MM. Appropriate experimental models have not been studied intensively to analyze the development of melanomas in locations corresponding to AM and MM. In CMA2 (Chen), the contribution of glutamatergic signaling to AM and MM will be investigated based on the compelling preliminary results presented in this application highlights the need to understand better these rare melanoma subtypes and glutamatergic signaling. Early AM and MM tumors in highly-relevant mouse models will be characterized to determine the involvement of EPAC signaling and McSC subtypes to the initiation and maintenance of these tumors. Experimental treatments will be applied to characterize their contributions upon tumors originating in locations analogous to acral and mucosal areas in humans. Finally, Veteran AM and MM samples will be studied to correlate AM and MM drivers with prognosis and treatment to develop improved approaches to detect and manage these rare tumors before irreversible progression.