Investigating the biology and therapeutic vulnerabilities of ER+ metastatic breast cancer with activating HER2 mutations

项目 摘要/摘要 候选人Utthara Nayar女士，博士，是一名翻译癌症生物学家，目前是 达纳-法伯癌症研究所、哈佛医学院和麻省理工学院博德研究所的医学 哈佛大学。她利用基因组技术研究雌激素受体的耐药机制- (ER+)转移性乳腺癌(MBC)。在此之前，她在病毒肿瘤学实验室接受培训 康奈尔大学和布里格姆妇女医院。她希望在大学继续她的学术生涯 将涉及分子和基因组的乳腺癌基础研究和翻译研究的交叉 方法，与内科科学家和致力于结束这种疾病的计算生物学家合作。 这项建议列出了一个有组织的三年研究和课程工作计划，包括获取数据 科学、拨款和翻译技能，这将使研究人员成为一名经验丰富的 实验生物学家和生物信息学家。该研究项目提出，结合 合作者和机构环境，旨在让她走上独立的道路 乳腺癌的治疗反应和耐药领域。 乳腺癌死亡的主要原因是耐药性的发展，尽管很大程度上未知 机制，到ER+MBC的靶向抗雌激素治疗。纳亚尔博士最近发现获得性激活 激活MAPK途径的人表皮生长因子受体2(HER2)的突变 与耐药，并证明这些直接授予耐药性的抗ER药物。因为这是一个 新兴的耐药性类别，对肿瘤的生物学和治疗脆弱性有了更深入的了解 在MAPK途径中携带这种突变或相关的基因改变是必需的。科学目标 这项建议的目的是从两个方面研究HER2突变对ER+MBC中MAPK信号的影响 纳亚尔博士通过ER+HER2的全球转录分析确定的主要生物学后果- 突变肿瘤：ER途径改变，干扰素和炎症信号增强。此应用程序 建议从两个不同的目标来研究这些问题。在特定的目标1中，HER2突变对 内质网相关和全球转录网络将使用基因组规模的体外方法进行检测 (CHIP-SEQ/ATAC-SEQ)目的2确定增强的炎症信号在ER+HER2中的意义 突变肿瘤，通过确定自分泌和旁分泌对细胞系信号和免疫原性的影响 和小鼠模型系统，以及通过检测肿瘤患者的肿瘤免疫微环境 样本。在项目结束时，我们可以预期对HER2突变和相关的 MAPK激活对ER信号和免疫原性的影响及其在乳腺肿瘤中的作用 表观遗传学(目标1)或免疫治疗(目标2)方法的靶向性潜力。

Project Summary/Abstract The candidate, Ms. Utthara Nayar, PhD, is a translational cancer biologist, and currently a Research Fellow in Medicine at Dana-Farber Cancer Institute, Harvard Medical School, and the Broad Institute of MIT and Harvard. She employs genomic technology to investigate mechanisms of resistance in estrogen receptor- expressing (ER+) metastatic breast cancer (MBC). Prior to this, she trained in viral oncology laboratories at Cornell University and Brigham and Women's Hospital. She expects to pursue an academic career at the intersection of basic and translational research in breast cancer that will involve molecular and genomic approaches, in collaboration with physician-scientists and computational biologists working to end the disease. This proposal lays out a structured 3-year plan of research and coursework, including the acquisition of data science, grant-writing, and translational skills, which will uniquely situate the investigator as an experienced experimental biologist and bioinformatician. The research project proposed, in combination with the team of collaborators and institutional environment, is designed to position her on a road to independence within the field of therapeutic response and resistance in breast cancer. The primary reason for breast cancer mortality is the development of resistance, through largely unknown mechanisms, to targeted anti-estrogen therapies in ER+ MBC. Dr. Nayar recently identified acquired activating mutations in human epidermal growth factor receptor 2 (HER2), which activates the MAPK pathway, in patients with resistance, and demonstrated that these directly conferred resistance to anti-ER agents. Since this is an emerging class of resistance, a deeper understanding of the biology and therapeutic vulnerabilities of tumors bearing such mutations or related genetic alterations in the MAPK pathway is required. The scientific objective of this proposal is to study the effect of MAPK signaling from HER2 mutations in ER+ MBC in terms of two major biological consequences that Dr. Nayar identified through global transcriptomic analysis in ER+ HER2- mutant tumors: altered ER pathway, and enhanced interferon and inflammatory signaling. This application proposes to investigate these questions in two distinct aims. In specific Aim 1, the effect of HER2 mutations on the ER-associated and global transcriptional network will be examined using genome-scale in vitro approaches (ChIP-seq/ATAC-seq). Aim 2 determines the implication of enhanced inflammatory signaling in ER+ HER2- mutant tumors, by ascertaining the autocrine and paracrine effects on signaling and immunogenicity in cell line and mouse model systems, as well as by examining tumor immune microenvironment in patient tumor samples. At the end of the project, we can expect to gain a deeper understanding of HER2-mutant and related breast tumors in terms of the effect of MAPK activation on ER signaling and immunogenicity, as well as their potential for targetability by epigenetic (Aim 1) or immunotherapeutic (Aim 2) approaches.