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

描述（由申请人提供）：针对BRAF/MAPK通路的靶向治疗是治疗黑色素瘤的一种令人兴奋的新治疗方法。然而，尽管初始反应率很高，但反应的持续时间有限。尽管初步证据表明，致癌BRAF（存在于60%的黑色素瘤中）可能通过抑制黑素细胞分化抗原和增加免疫抑制细胞因子的产生来促进免疫逃逸，但这可能是由于不同致癌途径的冗余和信号传导所致。在了解致癌BRAF如何促进黑色素瘤的免疫逃逸方面存在根本性的差距，更好地了解这种动态相互作用可能会导致治疗的进步。本提案的长期目标是更好地了解黑色素瘤中致癌BRAF和BRAF抑制的下游信号反应和免疫反应。这项特殊应用的目的是在体外和体内BRAF突变黑色素瘤模型中，以及在接受BRAF抑制剂治疗的转移性黑色素瘤患者中研究这些反应。核心假设是，致癌BRAF通过下调黑素细胞分化抗原和增加免疫抑制细胞因子的产生，促进黑色素瘤的免疫逃逸。这个假设是根据候选人在导师的指导下产生的初步数据制定的。提出这项研究的基本原理是，靶向BRAF抑制和免疫治疗的结合将改善黑色素瘤的治疗策略，最终可能扩展到其他BRAF突变癌症。这一假设将通过追求两个特定目标来验证：1)在体外和体内研究用MAPK途径抑制或BRAFV600E选择性抑制剂治疗BRAF突变黑色素瘤的下游信号反应；2)在体外和体内研究黑色素瘤对MAPK / BRAF抑制的免疫应答机制。在这些目标下，现有的试剂和资源将使用申请人手中可行的既定技术来询问信号通路和免疫反应。这种方法是创新的，因为它将黑色素瘤遗传学和免疫治疗领域联系起来，目的是通过更好地了解致癌突变和免疫逃逸之间复杂的相互作用，提供新的治疗选择。这项拟议的研究意义重大，因为它有望为治疗braf突变型黑色素瘤提供新的治疗策略，并有机会研究和应用我们所学到的治疗其他braf突变型癌症。

DESCRIPTION (provided by applicant): 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.