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

研究激活 HER2 突变的 ER 转移性乳腺癌的生物学和治疗脆弱性

基本信息

批准号：
10624281
负责人：
Utthara Nayar
金额：
$ 18.89万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624281
关键词：
ATAC-seq Antiestrogen Therapy Basic Science Binding Biological Biological Models Biology Breast Cancer Cell Cell Line Cells ChIP-seq Clinic Clinical Collaborations Dana-Farber Cancer Institute Data Data Science Development Disease Doctor of Philosophy Effectiveness Elements Endocrine Environment Epidermal Growth Factor Receptor Epigenetic Process Estrogen Antagonists Estrogen Nuclear Receptor Estrogen Receptors Estrogen receptor positive Gene Expression Profile Genes Genetic Transcription Genomic approach Genomics Goals Grant Growth Factor Hospitals Human Immune system Immunologic Markers Immunotherapeutic agent Immunotherapy In Vitro Incidence Individual Inflammatory Institution Interferons Laboratories MAP Kinase Gene Malignant Neoplasms Mammary Neoplasms Medicine Metastatic breast cancer Mitogen-Activated Protein Kinases Molecular Mutation Oncology Organoids Pathway interactions Patients Pharmaceutical Preparations Physicians Positioning Attribute Receptor Signaling Regulation Research Research Personnel Research Project Grants Resistance Resistance development Role Sampling Scientist Signal Transduction Stains Structure Technology Testing Therapeutic Toxic effect Training Transactivation Translational Research Universities Viral Woman Work Writing autocrine cancer cell cancer therapy career cell type combinatorial data acquisition design experience genome-wide immune checkpoint blockade immunogenicity in vivo individualized medicine malignant breast neoplasm medical schools mortality mouse model mutant neoplastic cell novel therapeutics paracrine personalized medicine precision medicine programs promoter resistance mechanism response single-cell RNA sequencing skills targeted treatment therapy resistant transcriptome sequencing transcriptomics treatment choice treatment response tumor tumor-immune system interactions

项目摘要

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.

项目摘要/摘要候选人 Utthara Nayar 女士博士是一位转化癌症生物学家，目前是丹纳法伯癌症研究所、哈佛医学院和麻省理工学院博德研究所的医学哈佛。她利用基因组技术来研究雌激素受体的耐药机制表达（ER+）转移性乳腺癌（MBC）。在此之前，她在病毒肿瘤学实验室接受过培训康奈尔大学和布莱根妇女医院。她希望在该大学从事学术生涯乳腺癌基础研究和转化研究的交叉点，涉及分子和基因组方法，与医师科学家和计算生物学家合作，致力于终结这种疾病。该提案制定了一个结构化的 3 年研究和课程计划，包括数据采集科学、资助写作和翻译技能，这将使研究者成为经验丰富的独特者实验生物学家和生物信息学家。与团队合作提出的研究项目合作者和制度环境，旨在使她走上独立之路乳腺癌的治疗反应和耐药性领域。乳腺癌死亡的主要原因是耐药性的产生，这种耐药性是通过很大程度上未知的方式产生的 ER+ MBC 的靶向抗雌激素治疗。 Nayar 博士最近发现获得性激活患者体内人类表皮生长因子受体 2 (HER2) 发生突变，该受体可激活 MAPK 通路具有耐药性，并证明这些直接赋予抗 ER 药物的耐药性。由于这是一个新兴的耐药性，对肿瘤生物学和治疗脆弱性的更深入了解需要在 MAPK 途径中携带此类突变或相关遗传改变。科学目标该提案的目的是从以下两个方面研究 ER+ MBC 中 HER2 突变对 MAPK 信号传导的影响 Nayar 博士通过 ER+ HER2- 的整体转录组分析确定了主要的生物学后果突变肿瘤：ER途径改变，干扰素和炎症信号传导增强。这个应用程序提议以两个不同的目标来研究这些问题。在具体目标 1 中，HER2 突变对将使用基因组规模的体外方法检查与 ER 相关的全局转录网络（ChIP-seq/ATAC-seq）。目标 2 确定 ER+ HER2- 中炎症信号传导增强的影响突变肿瘤，通过确定自分泌和旁分泌对细胞系信号传导和免疫原性的影响和小鼠模型系统，以及通过检查患者肿瘤中的肿瘤免疫微环境样品。在项目结束时，我们有望对 HER2 突变体及相关突变有更深入的了解 MAPK 激活对 ER 信号传导和免疫原性的影响及其对乳腺肿瘤的影响表观遗传（目标 1）或免疫治疗（目标 2）方法的靶向性潜力。