Overcoming BRAF-inhibitor Resistance in Melanoma

描述(申请人提供)：BRAF抑制剂疗法已经显示出存活率的改善，并且从首次报道BRAFV600E突变到大约一半的黑色素瘤还不到十年，就获得了FDA的批准。这一创纪录的药物开发时间证明了这种新治疗模式的高度相关性。然而，最初的成功受限于对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赠款(PPG)，包括四个项目，重点是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。我们纳入了最初综述中的批评和关注，并通过以下项目和核心提供了明显改进的应用：项目1(LO)提出了一项关于获得性耐药途径的全面研究，作为使用集成基因组平台与功能实验相结合的组合治疗的目标。项目2(Graeber)使用基于质谱学的磷酸图谱和蛋白质相互作用图谱技术，从系统的角度表征驱动抗性的信号事件。项目3(Tseng)建议使用微流控诊断工具箱来量化多个信号和基因组事件，该工具箱针对可重复采样的微创技术进行优化，以研究对BRAF抑制剂的获得性耐药性过程。项目4(Ribas)在动物模型和临床上测试了BRAF抑制剂疗法和免疫疗法的结合，以防止对单一药物BRAF抑制剂的耐药性。 行政核心A将为私营部门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学支助。Biospecimen和病理核心B作为内部产生的和具有致癌特征的黑色素瘤细胞系的储存库，将处理和提供使用BRAF抑制剂治疗的患者的新活检组织。项目整合是通过一组高度合作的研究人员解决对BRAF抑制剂的耐药性的共同(但不重叠的)科学目标来实现的。

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.