The overall goals of the Yale SPORE in Skin Cancer (YSPORE) are to improve prevention, diagnosis and treatment of melanomas by performing translational studies in four subjects: a) (Genomic sunlight dosimeters for melanoma prevention (Project 1);b) The B7-H1/PD-1 pathway in melanoma immunity (Project 2);c) Molecular diversity of melanomas and response to targeted (Project 3);and d) The RACil pathway as a target for melanoma therapy (Project 4). The program includes Developmental Research and Career Development Programs, Biospecimen Resource and Bioinformatics/Biostatistics Cores that support the translational research needs of all investigators in the YSPORE. The YSPORE is led by an Administration Core that coordinates and manages the program on a daily basis. 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 (Project 3) and in a novel RAC1 pathway that we have identified in melanoma (Project 4). Project 2 is dedicated to one of the most promising immunotherapy for melanoma, anti PD-1, and is focused on tumor/stroma interactions to reveal mechanism of evasion of cancer immunity. The studies in this project should have direct impact for current development of B7-H1/PD-1 blockade as a novel and promising approach for melanoma therapy. 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 the "RAC1 pathway";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.

Public Health Relevance

The studies will address major questions in melanoma: 1) Can cumulative carcinogenic sunlight exposure can be measured as DNA damage and mutations in individual's skin? 2) Can melanomas be classified based on mutations in specific networks? 3) Are there molecular markers that can predict a patient's response to targeted and immunotherapies? 4) Is the newly discovered RAC1 pathway can become an alternative therapeutic target?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA121974-06A1
Application #
8335667
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (M1))
Program Officer
Agarwal, Rajeev K
Project Start
2006-06-01
Project End
2017-08-31
Budget Start
2012-09-19
Budget End
2013-08-31
Support Year
6
Fiscal Year
2012
Total Cost
$2,300,000
Indirect Cost
$909,004
Name
Yale University
Department
Dermatology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Brash, Douglas E (2015) UV signature mutations. Photochem Photobiol 91:15-26
Jilaveanu, Lucia B; Parisi, Fabio; Barr, Meaghan L et al. (2015) PLEKHA5 as a Biomarker and Potential Mediator of Melanoma Brain Metastasis. Clin Cancer Res 21:2138-47
Kong, Yong; Krauthammer, Michael; Halaban, Ruth (2014) Rare SF3B1 R625 mutations in cutaneous melanoma. Melanoma Res 24:332-4
Taube, Janis M; Klein, Alison; Brahmer, Julie R et al. (2014) Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 20:5064-74
Zito, Giovanni; Saotome, Ichiko; Liu, Zongzhi et al. (2014) Spontaneous tumour regression in keratoacanthomas is driven by Wnt/retinoic acid signalling cross-talk. Nat Commun 5:3543
Leonhardt, Ralf M; Abrahimi, Parwiz; Mitchell, Susan M et al. (2014) Three tapasin docking sites in TAP cooperate to facilitate transporter stabilization and heterodimerization. J Immunol 192:2480-94
Sanmamed, Miguel F; Chen, Lieping (2014) Inducible expression of B7-H1 (PD-L1) and its selective role in tumor site immune modulation. Cancer J 20:256-61
Ho, Ping-Chih; Meeth, Katrina M; Tsui, Yao-Chen et al. (2014) Immune-based antitumor effects of BRAF inhibitors rely on signaling by CD40L and IFN?. Cancer Res 74:3205-17
Paglino, Justin C; Andres, Wells; van den Pol, Anthony N (2014) Autonomous parvoviruses neither stimulate nor are inhibited by the type I interferon response in human normal or cancer cells. J Virol 88:4932-42
Troche, Jose Ramon; Ferrucci, Leah M; Cartmel, Brenda et al. (2014) Systemic glucocorticoid use and early-onset basal cell carcinoma. Ann Epidemiol 24:625-7

Showing the most recent 10 out of 86 publications