SPORE HUMAN SKIN
The Specimen Resource Core is essential for the ongoing function of the Yale SPORE in Skin Cancer, including the above proposed continuing studies for Projects 1, 2, and 3. It: a) collects a large repertoire of specimens for translational and preclinical studies in melanoma, including melanocytic lesions, melanoma tumors and cells, normal skin, serum, and circulating lymphocytes b) ensures high quality control and proper long-term storage, annotation, and timely distribution of specimens to YSPORE-SC investigators c) establishes and maintains a central database of essential pathological, clinical, epidemiological, follow-up information and basic research data generated by the YSPORE-SC projects that is integrated with the Bioinformatics/Biostatistics Core d) provides special services such as the analysis of specimens from clinical trials, mutations, chromatin modification, and collection of TlLs (tumor infiltrating lymphocytes and e) maintains and distributes validated reagents (antibodies, oligonucleotides for PCR, DNA, RNA, plasmids, cell extracts) needed for molecular analyses of tumors by different YSPORE-SC investigators. Among the latest findings are: a) identifying the role of germ-line MC1R red-hair variants on increasing the mutation frequency in melanoma b) molecular characterization of triple WT melanomas and the identification of ‘driver’ genes that contribute to malignant transformation and c) perform genomic and transcriptomic assessments of clinical samples to correlate changes with prognosis and responses to therapy. The goals of his project are: a) to identify new targets for melanoma therapy and susceptibility to novel drugs b) to perform functional analyses on the best markers associated with treatment response employing melanoma cells in culture and c) to apply genomic and transcriptomic data to assess clinical samples and correlate with changes in responses to therapy. Project 3: Novel ‘Driver’ Mutations and Targetable Protein Kinases in Melanomas Median serum IL-8 levels decreased significantly in responding patients and increased at the moment of progression, when compared with baseline levels. One of the latest findings is that changes in serum IL-8 levels can be used to monitor and predict clinical benefit from immune checkpoint blockade in melanoma and NSCLC patients. In addition, the project continues ongoing studies of identifying markers and effector mechanisms to predict responses to immune checkpoint inhibitors. The goals of his project are: a) to assess the association between B7-H1/PD-1 expression in the human melanoma microenvironment with clinical response to anti-PD-1 therapy b) to study effector mechanisms of the B7-H1/PD-1 blockade in augmenting anti-melanoma immunity and in melanoma regression and c) to maximize melanoma therapeutic immune sensitivity by mechanism-based combinatory approaches. Project 2: The PD-1/B7-H1 Pathway and Melanoma Immunity One of the project's major accomplishments is showing that pigmented melanocytes continue to produce UV-like DNA photoproducts in the dark via “chemiexcitation” that may lead to genome instability and cancer development. The results of these studies will enable the development of a clinically actionable assay for a patient's sun exposure history and resulting melanoma risk.
The main goals of this project are: a) to map human genomic regions that are UV damage hotspots or DNA repair slow spots b) to quantitate rare UV-mutated genes in skin in vivo and c) to use genomic regions sensitive to UV photoproducts and mutations as dosimeters to correlate cumulative sunlight exposure in normal skin to risk for melanoma. The supplement funds support the following projects and cores: Project 1: Genomic Sunlight Dosimeters for Melanoma Prevention The YSPORE-SC is currently supported by Administrative Supplement to bridge the one-year gap for our new competitive renewal application. The overriding themes are to reveal biomarkers and targets for therapy based on information from analyses of Next-Generation DNA sequencing (NGS), genomics, transcriptomics and proteomics.
The overall goals of the Yale SPORE in Skin Cancer (YSPORE-SC) are to improve prevention, diagnosis and treatment of melanomas.