Identification of Resistance-Conferring Stromal Alterations in BRAF Mutant Melano

这个项目将对目前存在的分子变化进行全面分类 在黑色素瘤间质中设置BRAF靶向治疗。全球转录组，表观基因组 蛋白质组学分析将在人类和小鼠的BRAF突变体中产生无偏见的图谱 黑色素瘤包括配对的基线和治疗后或复发样本。这些一体化的 跨物种比较分析将定义候选驾驶员基质改变，这种改变可能 口述对BRAF靶向治疗的反应。候选事件的功能相关性将 通过对靶标或其规范的遗传或药物扰动进行验证 体外和体内途径。此外，将通过以下方式确认人类相关性 对大量带注释的人类黑色素瘤样本的分析。超越了发现和 验证，我们将阐明潜在的机制，目标是将这些见解转化为 合理的治疗组合旨在中和肿瘤和间质靶点 避免/尽量减少BRAFi阻力的出现。

This project will comprehensively catalogue the molecular alterations present in melanoma stroma in the setting of BRAF targeted therapy. Global transcriptomic, epigenomic and proteomic analyses will generate an unbiased profile in both human and mouse BRAF-mutant melanomas including paired baseline and post-treatment or relapse samples. These integrative and cross-species comparative analyses will define candidate driver stromal alterations that may dictate the response to BRAF targeted therapy. The functional relevance of candidate events will be validated through genetic or pharmacologic perturbation of the targets or their canonical pathways in vitro and in vivo. Further, confirmation of human relevance will be obtained through analysis of a large cohort of annotated human melanoma samples. Beyond discovery and validation, we will elucidate underlying mechanisms with the goal of converting these insights into rational therapeutic combinations designed to neutralize both tumor and stromal targets and avoid/minimize the emergence of BRAFi resistance.