Yale SPORE in Skin Cancer

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OVERALL: PROJECT SUMMARY The Yale SPORE in Skin Cancer (YSPORE), now in its third funding cycle, involves a broad range of projects and investigators with diverse expertise, whose goal is to decrease mortality from melanoma by developing novel drugs and regimens to treat patients once it metastasizes and develop predictive biomarkers to select patients for the optimal treatment regimen. YSPORE leans on the immense scientific and clinical strengths at Yale School of Medicine and Yale Cancer Center including immunobiology, genetics, epigenetics, quantitative sciences, immuno-oncology, animal models, and digital pathology. YSPORE investigators have made major contributions in recent years to developing improved immune therapy approaches for melanoma patients with advanced disease and novel single cell tumor profiling platforms. Advances in systemic therapies for advanced melanoma, particularly immune checkpoint inhibitors, that prolong survival, pose a new set of challenges for clinicians which will be addressed by the proposed research program, as we strive to increase the long term survival for all melanoma patients. The YSPORE translational research team proposes to accomplish the objective of decreasing morbidity and mortality from skin cancer through four specific aims: Specific Aim 1: Develop new approaches to enhancing activity of PD-1 inhibitors by co-targeting the innate and adaptive immune systems in immune checkpoint inhibitor naïve patients; Specific Aim 2: Study novel drugs that target the epigenetic modifier KDM5B, to upregulate endogenous retroelements and enhance T cell infiltration in tumors that are unresponsive or poorly responsive to immune checkpoint inhibitors; Specific Aim 3: Study novel cytokines to overcome resistance to immune checkpoint inhibitors in patients whose melanoma has progressed on anti-PD-1; and Specific Aim 4: Develop new research directions to decrease mortality from melanoma and nurture the next generation of translational investigators focusing on skin cancer through a Developmental Research Program and a Career Enhancement Program. We propose three cores (Administrative Core, Biospecimen Core and Biostatistics and Bioinformatics Core) to support the projects, their clinical aims, mechanistic studies, and biomarker development for clinical application. The Projects and Cores are designed to be highly coordinated with the goal of maximizing resources and potential impact. New collaborations will be established during the funding period through the Developmental Research Program with the support of the Administrative Core. Collaborations with other institutions and skin cancer SPORE sites will be fostered by the Administrative Core. These coordinated efforts will enhance analysis of patient samples, use of cell cultures and animal models, and development of predictive biomarker assays. Our purpose is to translate the innovative approaches proposed here to clinical therapies for treatment of advanced skin cancer.