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：
9977376
负责人：
Utthara Nayar
金额：
$ 19.52万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9977376
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 Institutes Interferons Laboratories Lead Light 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 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 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

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 Institutes Interferons Laboratories Lead Light 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 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 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

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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女士博士是转化的癌症生物学家，目前是达纳 - 法伯癌症研究所，哈佛医学院和麻省理工学院的医学哈佛大学。她采用基因组技术来研究雌激素受体的抗性机制表达（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康奈尔大学和杨百翰和妇女医院。她希望在乳腺癌基本和转化研究的交集将涉及分子和基因组与医师科学家和计算生物学家合作，致力于结束这种疾病。该提案阐明了一项结构化的研究和课程计划，包括获取数据科学，授予写作和翻译技能，将独特地将调查员视为经验丰富的实验生物学家和生物信息学家。研究项目提出了，结合了团队合作者和机构环境旨在将她定位在通往独立之路的道路上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抗药性的发展，这在很大程度上未知机制，用于ER+ MBC中的靶向抗雌激素疗法。纳亚尔博士最近确定了获得的激活人类表皮生长因子受体2（HER2）的突变激活了MAPK途径的患者中的突变具有抵抗力，并证明了这些直接赋予对抗ER药物的抗性。因为这是一个新兴的抗药性类别，对肿瘤的生物学和治疗脆弱性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。科学目标该建议的是研究ER+ MBC中HER2突变的MAPK信号传导的效果 Nayar博士通过ER+ HER2-中的全球转录组分析确定的重大生物学后果突变肿瘤：改变ER途径，干扰素和炎症信号的增强。此应用程序建议以两个不同的目的调查这些问题。在特定目标1中，HER2突变对将使用基因组规模的体外方法检查与ER相关和全球转录网络（chip-seq/atac-seq）。 AIM 2决定了ER+ HER2-的炎症信号的增强的意义突变肿瘤，通过确定细胞系中信号传导和免疫原性的自分泌和旁分泌作用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，我们可以期望对HER2突变和相关的更深入了解就MAPK激活对ER信号传导和免疫原性的影响而言，乳腺肿瘤及其通过表观遗传学（AIM 1）或免疫治疗方法（AIM 2）方法实现目标性的潜力。