Mechanisms of non-genetic variation in melanoma

黑色素瘤非遗传变异的机制

• 批准号: 10749208
• 负责人: Salil Garg
• 金额: $ 16.07万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749208
• 关键词: Mechanisms; non; genetic; variation; melanoma

Project Summary/Abstract This proposal details a five year training plan for the development of a research program focused on non-genetic mechanisms of therapy resistance in melanoma. Therapies that target the MAPK pathway in melanoma have remarkable success in shrinking patients’ initial tumors but disease recurs, often without new mutations that explain therapy failure. This appears to be due to a small population of rare cells present in the initial tumor that display high levels of resistance genes such as epidermal growth factor receptor (EGFR) and are not killed by initial MAPK targeted therapy. The mechanisms that drive formation of these rare pre-resistant cells are unknown, though preliminary studies implicate gene regulation by enhancers. The goals of this research proposal are to characterize the key genetic pathways that define pre-resistant cells in patient tumors, identify enhancers that drive expression of resistance genes and cellular variation, and to identify pharmacologic targets for preventing therapy resistance. Since EGFR plays an important role in many cancers and non-genetic variation appears to undergird treatment failure in many different malignancies, the implications of this work for human disease may be far-reaching. The work will be mentored by Phillip A. Sharp at the Massachusetts Institute of Technology, a leader in understanding gene regulation in cancer and whose laboratory has produced numerous distinguished alumni. I am a practicing molecular pathologist at the Massachusetts General Hospital interested in how variation arises naturally within biological systems. In diagnostic pathology, we are attempting to achieve ever greater ‘personalized medicine’ in cancer treatment using sequencing. To achieve the best precision medicine possible, we must understand the mechanisms by which tumors evade therapy that go beyond genetic changes such as mutations. This will allow us to build better, more accurate diagnostics and give our oncologist colleagues the best actionable information. My career objective during the proposal period is to obtain a tenure-track position at an academic medical center continuing work as a Principal Investigator. Specifically, during the proposal period I will gain experience with melanoma model systems, enhancer biology, genomics, and systems biology approaches. My long term objective is to define how variation and heterogeneity arise within biological systems and how we can diagnose and manipulate these processes in human disease.

项目概要/摘要 该提案详细介绍了一项旨在开发研究计划的五年培训计划，重点关注 针对黑色素瘤治疗耐药的非遗传机制。 在黑色素瘤中，在缩小患者的初始肿瘤方面取得了显着的成功，但疾病经常复发 没有新的突变可以解释治疗失败，这似乎是由于少数稀有人群造成的。 初始肿瘤中存在的细胞显示出高水平的耐药基因，例如表皮生长 因子受体 (EGFR) 且不会被初始 MAPK 靶向治疗杀死 驱动机制。 这些罕见的前抗性细胞的形成尚不清楚，但初步研究表明基因 本研究提案的目标是表征关键的遗传特征。 定义患者肿瘤中的预耐药细胞的途径，识别驱动表达的增强子 耐药基因和细胞变异，并确定预防治疗的药理学靶点 由于 EGFR 在许多癌症中发挥着重要作用，而且非遗传变异似乎也发挥着重要作用。 强调许多不同恶性肿瘤的治疗失败，这项工作对人类的影响 这项工作将由马萨诸塞州的菲利普·夏普 (Phillip A. Sharp) 指导。 理工学院，在理解癌症基因调控方面处于领先地位，其实验室已 培养了众多杰出校友。 我是马萨诸塞州总医院的一名执业分子病理学家，对如何 在诊断病理学中，变异是自然产生的。 使用测序在癌症治疗中实现更大的“个性化医疗”。 尽可能最好的精准医学，我们必须了解肿瘤逃避治疗的机制 超越诸如突变之类的基因变化，这将使我们能够构建更好、更准确的产品。 诊断并为我们的肿瘤科医生同事提供最佳的可行信息 我的职业目标。 提案期间的目标是在学术医疗中心获得终身职位 具体来说，在提案期间我将积累经验。 黑色素瘤模型系统、增强子生物学、基因组学和系统生物学方法。 术语目标是定义生物系统中变异和异质性是如何产生的，以及我们如何 可以诊断和操纵人类疾病的这些过程。