Yale SPORE in Skin Cancer

The overall goals of the Yale SPORE in Skin Cancer (YSPORE) are to improve prevention, diagnosis and treatment of melanomas. Melanoma is the 5th most common cancer, constituting 5% of total cancer incidence. It is highly devastating, because there is no effective therapy once the disease has spread beyond the primary site. The YSPORE focuses on translational studies in four subjects: a) Genomic sunlight dosimeters for melanoma prevention; b) The B7-H1/PD-1 pathway in melanoma immunity(Project 2); Molecular diversity of melanomas and response to targeted therapy; and d) New pathways as a target for melanoma therapy.

One of the overriding themes of the YSPORE is to reveal biomarkers and targets for therapy based on information from Next-Generation (Next-Gen) DNA sequencing, genomics and proteomics analyses. This approach will be used to identify: 1) regions of the genome that are sensitive indicators of long-term accumulation of DNA damage and mutations resulting from sunlight exposure; and 2) the molecular basis of resistance of melanomas to targeted therapy with BRAF inhibitors (BRAFi). We will use structure-function analyses to identify druggable targets in resistant cells, and in novel pathways that we have identified in melanoma. The YSPORE studies include the most promising immunotherapy for melanoma, anti PD-1, and are focused on tumor/stroma interactions to reveal mechanism of evasion of cancer immunity. The expected translational outcomes of the program are: 1) Development of biological indicators for sun exposure risk to be used in melanoma prevention; 2) The identification of predictive biomarkers for therapeutic blockade of the PD-1/PD-L1 pathway and the role of this pathway in resistance to other types of immunotherapy, leading to potentially more effective combination immunotherapy; 3) The development of molecular tests that will guide treatment for BRAFi; 4) The classification of melanoma according to therapeutic options based on mutations in ‘driver’ pathway; 5) identification of small molecule that can target novel pathways; 6) The implementation of new national initiatives such as the CaTISSUE, The Cancer Genome Atlas (TCGA) and the MRF National Consortium for melanoma clinical trials.