Yale SPORE in Skin Cancer

The overall goals of the Yale SPORE in Skin Cancer (YSPORE-SC) are to improve prevention, diagnosis and treatment of melanomas. 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 YSPORE-SC is currently supported by Administrative Supplement to bridge the one-year gap for our new competitive renewal application. The supplement funds support the following projects and cores:

Project 1: Genomic Sunlight Dosimeters for Melanoma Prevention

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 results of these studies will enable the development of a clinically actionable assay for a patient's sun exposure history and resulting melanoma risk. 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.

Project 2: The PD-1/B7-H1 Pathway and Melanoma Immunity

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. In addition, the project continues ongoing studies of identifying markers and effector mechanisms to predict responses to immune checkpoint inhibitors. 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. Median serum IL-8 levels decreased significantly in responding patients and increased at the moment of progression, when compared with baseline levels.

Project 3: Novel ‘Driver’ Mutations and Targetable Protein Kinases in Melanomas

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. 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.

Core 2: Specimen Resource Core

The core performs several functions. 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. 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. In particular, the collection, processing, annotation, and genomic analysis of clinical specimens and isolation of TILS are needed. The Specimen Resource Core provides reagents to non-YSPORE-SC investigators as well. Requests should be addressed to Antonella Bacchiocchi, who is the manager of the Specimen Resource Core.

Core 3: Biostatistics/Bioinformatics Core

The goals of this core are to collect, store and analyze clinical and experimental data for YSPORE-SC projects, to maintain and extend the YSPORE-SC Data Management and Analysis System (DMAS) for specimen tracking, and bioinformatics and statistical analysis of YSPORE-SC project data. These activities are performed by Drs. Michael Krauthammer and James Knight.

Drs. Harriet Kluger and Marcus Bosenberg are the Principal Investigators of the multi-faceted program. The co-leaders of the projects and cores are Douglas Brash, Michael Krauthammer, Ruth Halaban, Mario Sznol, Lieping Chen, Yossi Schlessinger and Titus Boggon. The dedicated melanoma surgeons are Drs. Mario Sznol, James Clune, Sajid Khan, David Leffell, Kelly Olino, Kathleen Suozzi, Jean Bolognia, Marcus Bosenberg, Suguru Imaeda, Jonathan Leventhal, Shawn Cowper, Anjela Galan, Earl Glusac, Christine Ko, Jennifer McNiff, David Fischer, Jeffrey Ishizuka, Luica Jilaveanu, Harriet Kluger, Thuy Tran, Sarah Weiss, James Hansen, Jonathan Kirsch, David Madoff, Ami Rubinowitz, Ruth Halaban, and Patricia LaRusso who continue to provide the specimens needed for the studies.