Mechanisms of non-genetic variation in melanoma

黑色素瘤非遗传变异的机制

基本信息

批准号：
10474970
负责人：
Salil Garg
金额：
$ 3.45万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2022-10-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10474970
关键词：
Academic Medical Centers Adjuvant Therapy Automobile Driving Bar Codes Biological Models Biology Bromodomain CDKN2C gene Cell Count Cell Line Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats DNA Sequence Alteration Data Development Plans Diagnosis Diagnostic Disease Enhancers Epidermal Growth Factor Receptor Epigenetic Process Event Exposure to FGFRL1 gene Gene Expression Gene Expression Regulation General Hospitals Genes Genetic Genomics Goals Heterogeneity Institutes Laboratories Libraries MAP Kinase Gene Malignant Neoplasms Massachusetts Melanoma Cell Mentors Molecular Mutation Oncologist Pathologist Pathology Pathway interactions Patients Pharmacology Play Population Positioning Attribute Principal Investigator Process Regulator Genes Reporting Research Research Proposals Resistance Role Sampling Secondary to System Systems Biology Techniques Technology Testing Time Training Treatment Failure Variant Work accurate diagnostics base biological systems cancer genetics cancer therapy career experience genome-wide human disease inhibitor insight interest melanoma non-genetic novel novel therapeutic intervention novel therapeutics personalized medicine precision medicine prevent programs resistance gene single-cell RNA sequencing success targeted treatment tenure track therapeutic target therapy resistant tumor

项目摘要

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.

项目摘要/摘要该提案详细介绍了针对研究计划的制定五年培训计划靶向MAPK途径的疗法的非遗传学机制在黑色素瘤中，在缩小患者的初始肿瘤方面取得了巨大的成功，但疾病经常复发，通常没有解释治疗失败的新突变。最初肿瘤中存在的细胞表现出高水平的抗性基因表皮生长因子受体（EGFR），并未通过最初的MAPK靶向治疗杀死。这些罕见的耐药前细胞的形成是未知的，坚硬的前研究暗示了基因增强剂的调节。定义患者肿瘤中耐药细胞的途径，识别增强子，以驱动表达的表达抗性基因和细胞变异，并确定预防治疗的药理学靶标由于EGFR在许多癌症中起重要作用，因此在许多不同的恶性肿瘤中，这项工作对人类的影响疾病可能是遥远的。技术研究所，理解癌症基因调节的领导者，其实验室已有产生了许多杰出的校友。我是马萨诸塞州一般霍斯皮塔尔（Hosspital）的分子病理学家，对如何感兴趣在诊断病理学中，自然会发生变化。在癌症治疗中获得更大的“个性化医学” 最好的精度药物可能会了解肿瘤逃避治疗的机制这超出了诸如叛变之类的遗传变化。诊断和肿瘤学家同意我的职业生涯在提案期间，要在继续的学术医疗中心获得终身任期职位作为Asprincipal研究者的工作。黑色素瘤模型系统，增强生物学，基因组学和系统生物学方法。术语目标是定义生物系统中的变异和异质性如何以及我们如何弄清楚可以在人类疾病中诊断和操纵这些过程。