Targeted therapy against the BRAF/MAPK pathway is an exciting new therapeutic approach for the treatment of melanoma. However despite high initial response rates, duration of response is limited. This may be due to redundancy and signaling through different oncogenic pathways, though preliminary evidence suggests that oncogenic BRAF (present in 60% of melanomas) may contribute to immune escape through suppression of melanocyte differentiation antigens and increased production of immunosuppressive cytokines. There is a fundamental gap in the understanding of how oncogenic BRAF contributes to immune escape in melanoma, and a better understanding of this dynamic interplay may lead to advances in treatment. The long term goal of this proposal is to better understand the downstream signaling responses and immune responses to oncogenic BRAF and BRAF inhibition in melanoma. The objective in this particular application is to study these responses in vitro and in an in vivo model of BRAF-mutant melanoma, as well as in patients with metastatic melanoma being treated with BRAF inhibitors. The central hypothesis is that oncogenic BRAF contributes to immune escape in melanoma through down-regulation of melanocyte differentiation antigens and increased production of immunosuppressive cytokines. This hypothesis has been formulated based on preliminary data produced by the candidate under the guidance of her mentor. The rationale for the proposed research is that combination of targeted BRAF inhibition and immunotherapy will lead to improved therapeutic strategies for the treatment of melanoma, which may ultimately be extended to other BRAF-mutant cancers. This hypothesis will be tested by pursuing two specific aims: 1) Examining downstream signaling responses in BRAF mutant melanoma treated with MAPK pathway inhibition or a selective inhibitor of BRAFV600E in vitro &in vivo;and 2) Exploring the mechanism of melanoma immune response to MAPK / BRAF inhibition in vitro &in vivo. Under these aims, reagents and resources already on hand will be used to interrogate signaling pathways and immune responses using established techniques feasible in the applicant's hands. The approach is innovative, because it connects the fields of melanoma genetics and immunotherapy with the intent of providing new therapeutic options through a better understanding of the complex interplay between oncogenic mutations and immune escape. The proposed research is significant, because it is expected to result in new therapeutic strategies for the treatment of BRAF-mutant melanoma with the opportunity to study and apply what we learn to the treatment of other BRAF-mutant cancers.

Public Health Relevance

The proposed research is relevant to public health because it will lead to a better understanding of the BRAF mutation and its relation to immune escape in melanoma. Importantly, insights gained may be applied to other BRAF-mutant cancers, and potentially to other oncogenic mutations. Thus, the proposed research is relevant to the part of the NIH's mission that pertains to the pursuit of fundamental knowledge about the nature and behavior of living systems and application of that knowledge to extend healthy life and reduce the burdens of illness and disability.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
7K08CA160692-03
Application #
8706085
Study Section
Subcommittee G - Education (NCI)
Program Officer
Perkins, Susan N
Project Start
2012-08-03
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
$142,560
Indirect Cost
$10,560
Name
University of Texas MD Anderson Cancer Center
Department
Surgery
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Wei, Spencer C; Levine, Jacob H; Cogdill, Alexandria P et al. (2017) Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade. Cell 170:1120-1133.e17
Szczepaniak Sloane, Robert A; Gopalakrishnan, Vancheswaran; Reddy, Sangeetha M et al. (2017) Interaction of molecular alterations with immune response in melanoma. Cancer 123:2130-2142
Qin, Yong; Petaccia de Macedo, Mariana; Reuben, Alexandre et al. (2017) Parallel profiling of immune infiltrate subsets in uveal melanoma versus cutaneous melanoma unveils similarities and differences: A pilot study. Oncoimmunology 6:e1321187
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:
Eskiocak, Banu; McMillan, Elizabeth A; Mendiratta, Saurabh et al. (2017) Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma. Cancer Discov 7:832-851
Cogdill, Alexandria P; Andrews, Miles C; Wargo, Jennifer A (2017) Hallmarks of response to immune checkpoint blockade. Br J Cancer 117:1-7
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
Cogdill, Alexandria P; Prieto, Peter A; Reuben, Alexandre et al. (2017) Gene Targeting Meets Cell-Based Therapy: Raising the Tail, or Merely a Whimper? Clin Cancer Res 23:327-329
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:
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

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