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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.

项目总结/摘要候选人Utthara Nayar女士，博士，是一位翻译癌症生物学家，目前是美国癌症研究所的研究员。医学在达纳法伯癌症研究所，哈佛医学院，和麻省理工学院的布罗德研究所，哈佛。她采用基因组技术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了培训，康奈尔大学和布里格姆妇女医院她希望在大学里从事学术事业，乳腺癌基础和转化研究的交叉，将涉及分子和基因组方法，与医生科学家和计算生物学家合作，致力于结束这种疾病。该提案列出了一个结构化的3年研究和课程计划，包括数据的获取科学，赠款写作和翻译技能，这将独特地使研究者成为经验丰富的研究者。实验生物学家和生物信息学家。该研究项目提出，结合团队的合作者和机构环境，旨在使她走上独立的道路，乳腺癌的治疗反应和耐药性领域。乳腺癌死亡率的主要原因是耐药性的发展，机制，ER+ MBC中的靶向抗雌激素治疗。纳亚尔博士最近发现获得性激活患者中激活MAPK通路的人表皮生长因子受体2（HER 2）突变具有抗性，并证明这些直接赋予对抗ER剂的抗性。由于这是一个新出现的耐药性，对肿瘤生物学和治疗弱点的更深入了解需要在MAPK途径中携带这种突变或相关的遗传改变。科学目标该建议的一个目的是研究ER+ MBC中HER 2突变的MAPK信号传导的作用， Nayar博士通过ER+ HER 2的全球转录组学分析确定的主要生物学后果- 突变型肿瘤：ER通路改变，干扰素和炎症信号增强。本申请建议在两个不同的目的调查这些问题。在具体目标1中，HER 2突变对 ER相关的和全局的转录网络将使用基因组规模的体外方法进行研究（ChIP-seq/ATAC-seq）。目的2确定增强的炎症信号传导在ER+ HER 2 - 1中的意义。突变型肿瘤，通过确定细胞系中自分泌和旁分泌对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，我们可以期望获得更深入的理解HER 2突变体和相关的乳腺肿瘤的MAPK激活对ER信号传导和免疫原性的影响，以及它们的通过表观遗传学（Aim 1）或免疫学（Aim 2）方法的靶向潜力。