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.

该项目将全面记录目前的分子改变 BRAF 靶向治疗中的黑色素瘤基质。全局转录组、表观基因组 蛋白质组学分析将在人类和小鼠 BRAF 突变体中生成无偏见的图谱 黑色素瘤，包括配对的基线和治疗后或复发样本。这些综合 跨物种比较分析将确定候选驱动基质改变，这些改变可能 决定对 BRAF 靶向治疗的反应。候选事件的功能相关性将 通过目标或其规范的遗传或药理学扰动进行验证 体外和体内途径。此外，人类相关性的确认将通过 对大量带注释的人类黑色素瘤样本进行分析。超越发现和 验证后，我们将阐明潜在机制，目标是将这些见解转化为 旨在中和肿瘤和基质靶标的合理治疗组合， 避免/尽量减少 BRAFi 耐药性的出现。