Mechanisms of non-genetic variation in melanoma

项目摘要/摘要 这项提案详细说明了一项五年培训计划，该计划旨在制定一项研究计划，重点是 黑色素瘤治疗抵抗的非遗传机制。针对MAPK通路的治疗 黑色素瘤在缩小患者最初的肿瘤方面取得了显著的成功，但疾病往往会复发 没有新的突变来解释治疗失败。这似乎是由于一小部分稀有的 在最初的肿瘤中存在的细胞，表现出高水平的抗性基因，如表皮生长 因子受体(EGFR)，并且不会被最初的MAPK靶向治疗杀死。驱动的机制 这些罕见的前耐药细胞的形成尚不清楚，尽管初步研究表明与基因有关 由增强剂进行监管。这项研究计划的目标是描述关键的基因 定义患者肿瘤中前耐药细胞的途径，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靶点 抵抗。由于EGFR在许多癌症中发挥重要作用，非遗传变异似乎 许多不同恶性肿瘤治疗失败的基础，这项工作对人类的影响 疾病可能影响深远。这项工作将由马萨诸塞州的菲利普·A·夏普指导 理工学院，了解癌症基因调控的领先者，其实验室 造就了无数杰出的校友。 我是马萨诸塞州总医院的一名执业分子病理学家，对如何 变异在生物系统内自然产生。在诊断病理学中，我们正试图 使用测序技术在癌症治疗中实现更大的“个性化医学”。要实现 最精确的医学，我们必须了解肿瘤逃避治疗的机制 这超越了基因变化，如突变。这将使我们能够构建更好、更准确的 并为我们的肿瘤学家同事提供最佳的可操作信息。我的职业目标 在提议期间，将在学术医学中心获得终身教职，继续 担任首席调查员。具体地说，在建议书期间，我将获得以下经验 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。我的龙 术语的目的是定义生物系统中如何产生变异和异质性，以及我们如何 可以诊断和操纵人类疾病的这些过程。

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.