Novel Immunomodulators for Melanoma Therapy

PROJECT SUMMARY As estimated by the National Cancer Institute, there are more than 900,000 people living with melanoma in the USA. Despite recent advances in melanoma drug discovery, the average overall survival of patients with late- stage metastatic melanoma is ~3 years. Instances of complete response are very rare; therefore, more life- prolonging therapies are needed. This suggests a need for new approaches and targets for melanoma drug discovery. Our recent in vivo proof-of-principle efficacy and toxicity studies using small molecules discovered by us demonstrated that spliceosomal proteins hnRNPH1 and H2 (H1/H2) can be targeted without overt and organ toxicity to induce melanoma-specific cell death that can address an unmet need for such novel therapeutic approaches. Additionally, our preliminary data suggest that modulation of H1/H2 expression in melanoma cells in vitro upregulates immunogenicity of melanoma cells and induces infiltration of immune cells in vivo which can be used for immunotherapy. Based on these considerations, we hypothesize that targeting of H1/H2 could be a much needed and effective broad-spectrum melanoma therapy. To test this hypothesis, we propose to (1) determine efficacy of spliceosomal inhibitors 2155-14 and 18 in in vivo models of human TWT melanoma, (2) determine the role of H1/H2 in human melanoma intra-cellular immune pathways, and (3) validate immune response to H1/H2 treatment in vivo in BRAF and NRAS murine melanoma models. Our team is uniquely positioned to successfully execute the Aims of this study. Profs. Minond and Beljanski have expertise in drug evaluation in animal and molecular studies. Overall, these studies will validate targeting spliceosomal proteins hnRNPH1 and H2 as a useful approach to melanoma targeted and immunotherapy.