Identification of Resistance-Conferring Stromal Alterations in BRAF Mutant Melano

BRAF 突变体 Melano 中赋予抗性的基质改变的鉴定

• 批准号: 8555325
• 负责人: LYNDA CHIN
• 金额: $ 21.27万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8555325
• 关键词: Aftercare; BRAF gene; Biological; Cancer Biology; Cataloging; Catalogs; Development; Engineering; Event; Genetic; Genomics; Goals; Human; Immune; In Vitro; Indium; Maintenance; Malignant Neoplasms; Molecular; Mus; Mutation; Pathway interactions; Process; Proteomics; Regulation; Relapse; Resistance; Role; Sampling; Stromal Neoplasm; Therapeutic; Tumor Suppressor Genes; Validation; angiogenesis; cancer cell; cancer genome; cell stroma; cohort; comparative; design; epigenomics; in vivo; insight; knowledge base; melanoma; mouse model; mutant; response; transcriptomics; tumor

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.

该项目将全面分类的分子改变 在BRAF靶向治疗的情况下，在黑色素瘤中。全球转录组，表观基因组 蛋白质组学分析将在人和小鼠BRAF突变物中产生无偏的特征 黑色素瘤，包括配对的基线和处理后或复发样品。这些综合性 跨物种比较分析将定义候选驱动器的基础变化 决定对BRAF靶向疗法的反应。候选活动的功能相关性将 通过目标或其规范的遗传或药理扰动来验证 体外和体内途径。此外，将通过 分析大量注释的人黑色素瘤样品。超越发现和 验证，我们将阐明基本机制，目的是将这些见解转化为 理性的治疗组合旨在中和肿瘤和基质靶标和 避免/最小化Brafi抗性的出现。