Abstract

This project will comprehensively catalogue the molecular alterations present in melanoma stroma in the setting of BRAF targeted therapy. Global transcriptomic, epigenomic and proteomic analyses will generate an unbiased profile in both human and mouse BRAF-mutant melanomas including paired baseline and post-treatment or relapse samples. These integrative and cross-species comparative analyses will define candidate driver stromal alterations that may dictate the response to BRAF targeted therapy. The functional relevance of candidate events will be validated through genetic or pharmacologic perturbation of the targets or their canonical pathways in vitro and in vivo. Further, confirmation of human relevance will be obtained through analysis of a large cohort of annotated human melanoma samples. Beyond discovery and validation, we will elucidate underlying mechanisms with the goal of converting these insights into rational therapeutic combinations designed to neutralize both tumor and stromal targets and avoid/minimize the emergence of BRAFi resistance.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA163125-02
Application #
8555325
Study Section
Special Emphasis Panel (ZCA1-SRLB-3 (O1))
Project Start
2011-09-21
Project End
2016-07-31
Budget Start
2012-09-05
Budget End
2013-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$212,693
Indirect Cost

  Institution

Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Roh, Whijae; Chen, Pei-Ling; Reuben, Alexandre et al. (2017) Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance. Sci Transl Med 9:
Reuben, Alexandre; Spencer, Christine N; Prieto, Peter A et al. (2017) Genomic and immune heterogeneity are associated with differential responses to therapy in melanoma. NPJ Genom Med 2:
Young, Helen L; Rowling, Emily J; Bugatti, Mattia et al. (2017) An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition. J Exp Med 214:1691-1710
Friedman, Adam A; Xia, Yun; Trippa, Lorenzo et al. (2017) Feasibility of Ultra-High-Throughput Functional Screening of Melanoma Biopsies for Discovery of Novel Cancer Drug Combinations. Clin Cancer Res 23:4680-4692
Juneja, Vikram R; McGuire, Kathleen A; Manguso, Robert T et al. (2017) PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity. J Exp Med 214:895-904
Smith, Michael P; Rowling, Emily J; Miskolczi, Zsofia et al. (2017) Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure. EMBO Mol Med 9:1011-1029
Kwong, Lawrence N; Zou, Lihua; Chagani, Sharmeen et al. (2017) Modeling Genomic Instability and Selection Pressure in a Mouse Model of Melanoma. Cell Rep 19:1304-1312
Reardon, David A; Gokhale, Prafulla C; Klein, Sarah R et al. (2016) Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model. Cancer Immunol Res 4:124-35
Peng, Weiyi; Chen, Jie Qing; Liu, Chengwen et al. (2016) Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy. Cancer Discov 6:202-16
Lesokhin, Alexander M; Ansell, Stephen M; Armand, Philippe et al. (2016) Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study. J Clin Oncol 34:2698-704

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