Investigating concurrent Ras-pathway inhibition to optimize response to anti-PD-1 therapy in NRAS-mutant melanoma

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Project Summary/Abstract Melanoma is the most deadly form of skin cancer in the United States, with approximately 100,000 new cases diagnosed annually. Patients diagnosed with metastatic melanoma have previously suffered an abysmal 5-year survival rate, but a novel class of therapeutics termed immune checkpoint inhibitors (ICI) have changed the landscape of melanoma treatment. ICI therapy is effective in up to 50% of metastatic melanoma patients regardless of driver mutation, but work is needed to improve outcomes for patients. One such strategy is to combine targeted therapies, such as those used in BRAF-mutant melanoma, with ICI therapy. However, this strategy is limited by significant toxicity in BRAF-mutant patients and is ineffective in the 20% of patients whose tumors harbor NRAS driver mutations. Preliminary results suggest that rigosertib, a novel Ras-pathway inhibitor currently in clinical trials in hematologic malignancy, may enhance anti-tumor immunity. Our preliminary data show that treatment of melanoma tumors in mice with rigosertib induces an inflammatory tumor microenvironment, with enriched total and CD8+ dendritic cells and CD45-MHCII+ cells, elevated levels of both CD4+ and CD8+ T cells, B cells and NK cells, but decreased levels of PD-1+ CD4+ T cells and tumor-infiltrating macrophages. Rigosertib-treated melanoma tumors exhibit increased frequency and density of CD4+ and CD8+ T cells but very low levels of T cell activation in the tumor microenvironment. However, CD8+ T cells are strongly activated in the tumor-draining lymph nodes of rigosertib-treated tumors compared to activation under vehicle treatment, suggesting a potent immunosuppressive effect mediated by tumor microenvironment. These preliminary data provide a strong therapeutic basis for the use of immune checkpoint inhibitors (e.g., anti-PD-1) in combination with rigosertib to enhance anti-tumor immunity and optimize the treatment of melanoma. This hypothesis will be addressed by: 1) developing a microbioreactor system for the co-culture of human NRAS-mutant melanoma organoids with patient- matched leukocytes to evaluate the treatment response of NRAS-mutant melanoma cells to the combination of rigosertib plus α-PD-1 therapy as compared to α-PD1 alone, and 2) generating humanized patient-derived xenograft mouse models to determine the treatment response of NRAS- mutant melanoma cells to the combination of rigosertib plus α-PD-1 therapy as compared to either therapy alone. These studies will evaluate a promising novel treatment strategy with highly translational relevance to melanoma patients while also establishing critical models for further preclinical studies of immunotherapy.