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

探索联合 BRAF 靶向治疗的协同作用

基本信息

批准号：
8383369
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
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-03 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8383369
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

项目摘要

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 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，尽管初始响应率很高，但响应持续时间有限。这可能是由于不同致癌途径的冗余和信号传导所致，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而有助于免疫逃逸。对致癌 BRAF 如何促进黑色素瘤免疫逃逸的理解存在根本性差距，更好地理解这种动态相互作用可能会带来治疗的进步。该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。这一特定应用的目的是研究 BRAF 突变黑色素瘤的体外和体内模型以及接受 BRAF 抑制剂治疗的转移性黑色素瘤患者的这些反应。核心假设是，致癌性 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，有助于黑色素瘤的免疫逃逸。这一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。拟议研究的基本原理是，靶向 BRAF 抑制和免疫疗法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具体目标来检验：1) 在体外和体内检查用 MAPK 通路抑制或 BRAFV600E 选择性抑制剂治疗的 BRAF 突变黑色素瘤的下游信号反应； 2) 体外和体内探索黑色素瘤免疫反应对 MAPK/BRAF 抑制的机制。根据这些目标，现有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传导途径和免疫反应。该方法具有创新性，因为它将黑色素瘤遗传学和免疫治疗领域联系起来，旨在通过更好地理解致癌突变和免疫逃逸之间复杂的相互作用来提供新的治疗选择。拟议的研究意义重大，因为它有望产生治疗 BRAF 突变黑色素瘤的新治疗策略，并有机会研究和应用我们所学到的知识来治疗其他 BRAF 突变癌症。