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Exploring synergy of combined BRAF-targeted therapy & immunotherapy for melanoma

Jennifer A. Wargo

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National Institutes of Health (NIH)
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.

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