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

探索联合 BRAF 靶向治疗的协同作用

• 批准号: 8522168
• 负责人: Jennifer A. Wargo
• 金额: $ 14.26万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-03 至 2013-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8522168
• 关键词: Address; Advisory Committees; Antigens; Award; BRAF gene; Behavior; Biopsy; Cell Line; Complex; Data; Development; Differentiation Antigens; Disease; Down-Regulation; Funding; Goals; Hand; Immune; Immune response; Immunologics; Immunosuppressive Agents; Immunotherapy; In Vitro; Incidence; Knowledge; Lead; Learning; Life; MAP Kinase Gene; MEKs; Malignant Neoplasms; Melanoma Cell; Mentors; Metastatic Melanoma; Mission; Modeling; Molecular; Mus; Mutate; Mutation; Nature; Oncogenic; Operative Surgical Procedures; Organism; Pathway interactions; Patients; Physicians; Production; Public Health; Publications; Reagent; Reporting; Repression; Research; Research Personnel; Resources; Scientist; Signal Pathway; Signal Transduction; Staging; T-Lymphocyte; Techniques; Testing; Therapeutic; Training Activity; Work; World Health; base; burden of illness; career development; cytokine; disability; genetic immunotherapy; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; insight; melanocyte; melanoma; mutant; novel; novel therapeutic intervention; novel therapeutics; response; treatment strategy; tumor

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.

描述（由申请人提供）：针对BRAF/MAPK途径的有针对性治疗是一种令人兴奋的新治疗方法，用于治疗黑色素瘤。然而，尽管初始响应率很高，但响应持续时间仍有限。尽管初步证据表明，通过不同的致癌途径通过不同的致癌途径传导，这可能是由于冗余和信号传导所致，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的免疫抑制性细胞因子而导致免疫逃脱。理解致癌性BRAF如何有助于黑色素瘤的免疫逃脱，对这种动态相互作用的理解可能会导致治疗方面的进步。该提案的长期目标是更好地了解黑色素瘤中对致癌BRAF和BRAF抑制的下游信号反应和免疫反应。该特定应用的目的是在体外和BRAF突变黑色素瘤的体内模型以及通过BRAF抑制剂治疗转移性黑色素瘤的患者中研究这些反应。中心假设是致癌BRAF通过下调黑色素细胞分化抗原和免疫抑制性细胞因子的产生增加，从而有助于黑色素瘤的免疫逃逸。该假设是基于候选人在导师的指导下产生的初步数据提出的。拟议研究的理由是，靶向BRAF抑制和免疫疗法的组合将改善治疗黑色素瘤的治疗策略，最终可能扩展到其他BRAF突变癌。该假设将通过追求两个具体目的来检验：1）检查接受MAPK途径抑制作用或BRAFV600E的选择性抑制剂的BRAF突变体性黑色素瘤中的下游信号反应反应，并在体外和体外进行了选择性抑制剂； 2）探索黑色素瘤对MAPK / BRAF抑制体外和体内抑制作用的机制。在这些目标下，已经使用的试剂和资源将用于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。该方法具有创新性，因为它将黑色素瘤遗传学和免疫疗法领域连接起来，并通过更好地理解致癌突变与免疫逃生之间的复杂相互作用来提供新的治疗选择。拟议的研究很重要，因为预计它将导致新的治疗策略来治疗BRAF突变药物黑色素瘤，并有机会研究和应用我们学到的知识来治疗其他BRAF突变癌。