Mechanisms of non-genetic variation in melanoma

项目总结/摘要 该提案详细说明了一项为期五年的培训计划，旨在开发一项研究计划，重点是 黑色素瘤治疗耐药性的非遗传机制。靶向MAPK通路的治疗 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， 没有新的突变导致治疗失败这似乎是由于一个小的人口罕见的 存在于初始肿瘤中的细胞显示高水平的抗性基因，如表皮生长 因子受体（EGFR），并且不被初始MAPK靶向治疗杀死。驱动我们的机制 这些罕见的前耐药细胞的形成是未知的，尽管初步研究表明基因 增强子的调节。这项研究计划的目标是描述关键的遗传学特征， 定义患者肿瘤中前耐药细胞的途径，鉴定驱动 耐药基因和细胞变异，并确定预防治疗的药理学靶点 阻力由于EGFR在许多癌症中起重要作用，非遗传变异似乎 在许多不同的恶性肿瘤的治疗失败的基础上，这项工作对人类的影响 疾病可能是深远的。这项工作将由菲利普A指导。夏普在马萨诸塞州 他是了解癌症基因调控的领导者，其实验室拥有 产生了许多杰出的校友。 我是马萨诸塞州总医院的一名执业分子病理学家， 变异在生物系统中自然产生。在诊断病理学中，我们试图 利用测序技术在癌症治疗中实现更大的“个性化医疗”。实现 要想获得最好的精准医学，我们必须了解肿瘤逃避治疗的机制， 超越了基因突变等基因变化这将使我们能够建立更好，更准确的 诊断，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 在建议期间，是在一个学术医疗中心获得终身职位， 担任主要研究者。具体而言，在提案期间，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。我漫长 术语目标是定义生物系统中的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中的这些过程。

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.