Overcoming BRAF-inhibitor Resistance in Melanoma

描述（由申请人提供）：BRAF抑制剂治疗已证明可改善生存率，并在约一半黑色素瘤中首次报告BRAFV600E突变后不到10年内获得FDA批准。这一创纪录的药物开发时间证明了这种新疗法的高度相关性。然而，最初的成功是有限的，对BRAF抑制剂的获得性耐药性的频繁发展。在这次重新提交中，我们提出了一个综合项目计划资助（PPG），其中四个项目集中在了解黑色素瘤如何对BRAF抑制剂产生耐药性以及如何设计组合策略来预防或治疗耐药性。我们已经纳入了初步审查的批评和关注，我们提供了一个显着改进的应用程序与以下项目和核心：项目1（Lo）提出了一个全面的研究获得性耐药途径作为目标的组合治疗使用集成的基因组平台加上功能实验。项目2（Graeber）使用基于质谱的磷酸化分析和蛋白质相互作用分析技术，从系统的角度来表征驱动抗性的信号事件。项目3（Tseng）提出使用微流体诊断工具箱来定量多种信号传导和基因组事件，针对适合重复采样的微创技术进行优化，以研究对BRAF抑制剂的获得性抗性的过程。项目4（Ribas）测试BRAF抑制剂疗法和免疫疗法的组合，以防止动物模型和临床中对单药BRAF抑制剂产生耐药性。 行政核心A将为项目编制小组的活动提供全面支助，包括全面的生物统计和生物信息支助。生物标本和病理学核心B作为内部生成和致癌性特征的黑色素瘤细胞系的储存库，将处理和提供来自接受BRAF抑制剂治疗的患者的新活检标本。通过一组高度合作的研究人员解决BRAF抑制剂耐药性的共同（但不重叠）科学目标实现项目整合。

DESCRIPTION (provided by applicant): BRAF inhibitor therapy has demonstrated an improvement in survival and has gained FDA approval less than ten years from the first reporting of the BRAFV600E mutation in approximately half of melanomas. This record drug development time attests to the high relevance of this new mode of therapy. However, the initial success is limited by the frequent development of acquired resistance to BRAF inhibitors. In this resubmission we propose an integrated project program grant (PPG) with four projects centered on the understanding of how melanomas become resistant to BRAF inhibitors and how combinatorial strategies can be designed to prevent or treat resistance. We have incorporated the critiques and concerns from the initial review and we provide a markedly improved application with the following projects and cores: Project 1 (Lo) proposes a comprehensive study of acquired resistance pathways as targets for combinatorial treatments using integrated genomic platforms coupled with functional experiments. Project 2 (Graeber) uses mass spectrometry-based phosphoprofiling and protein interaction profiling techniques to characterize the signaling events driving resistance from a systems perspective. Project 3 (Tseng) proposes the use of a microfluidic diagnostics toolbox for quantification of multiple signaling and genomic events, optimized for minimally invasive techniques amenable to repeated sampling, to study the process of acquired resistance to BRAF inhibitors. Project 4 (Ribas) tests the combination of BRAF inhibitor therapy and immunotherapy to prevent resistance to single agent BRAF inhibitors in animal models and in the clinic. The Administrative Core A will provide overall support for the activities of the PPG, including comprehensive biostatistics and bioinformatics support. The Biospecimen and Pathology Core B serves as a repository of in-house generated and oncogenically characterized melanoma cell lines and will process and provide new biopsies from patients treated with BRAF inhibitors. Program integration is achieved through the common (but non-overlapping) scientific goals of addressing resistance to BRAF inhibitors by a group of highly collaborative investigators.