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Therapeutic approaches to ER mutant breast cancer

ER突变乳腺癌的治疗方法

基本信息

批准号：
9238168
负责人：
Sarat Chandarlapaty
金额：
$ 39.21万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9238168
关键词：
Affinity Agonist Alleles Aromatase Inhibitors Automobile Driving Biochemical Biopsy CRISPR screen Cancer Patient Cause of Death Cell Line Cell Proliferation Cells Clinical Data Dependence Dimerization Disease Drug Targeting Drug resistance Estradiol Estrogen Receptor alpha Estrogen Receptors Estrogens Fulvestrant Gene Expression Genetic Transcription Goals Growth Heat-Shock Proteins 90 Hormones Human Impairment In Vitro Knock-in Ligand Binding Domain Ligands Malignant Neoplasms Modeling Molecular Conformation Mutation Organoids Outcome Pathway interactions Patients Pharmacology Phenotype Property Receptor Inhibition Recurrence Resistance Route Sampling Selective Estrogen Receptor Modulators Somatic Mutation Systemic Therapy Tamoxifen Testing Therapeutic Therapeutic Index United States Woman Xenograft Model clinically relevant deprivation dimer effective therapy genome-wide hormone therapy inhibitor/antagonist malignant breast neoplasm mutant neoplastic cell next generation novel programs receptor receptor function resistance mechanism response targeted cancer therapy therapy resistant tumor

项目摘要

Drugs targeting the estrogen receptor (ER) in breast cancer have been extremely successful in controlling the disease for many patients, however acquired resistance is frequently encountered. We have identified recurrent mutations in the ligand binding domain (LBD) of ER among a high percentage of patients with such acquired resistance. We have found that the two most frequent mutations promote an agonist conformation despite the absence of ligand, cause resistance to aromatase inhibitors (AI), associate with poor clinical outcomes, and may be targeted by certain ER antagonists. However, we have more recently found that a spectrum of clinical ESR1 mutations exists. Our data reveal that there is diversity in the mechanisms whereby different mutants alter ER function as well as diversity in the impact of different mutations on ER conformation and activity. The overall hypothesis of this project is that different ER LBD mutations share an ability to promote some level of estrogen-independent receptor activity but have distinctive potencies in driving tumor phenotypes and promoting drug resistance. In this proposal, we will establish the mechanisms whereby different ESR1 mutations promote ER activity, characterize the gene expression programs driven by different mutations, understand the implications of different mutations for sensitivity to ER inhibition, identify likely routes of resistance to ER antagonists in ER mutant disease, and develop rational combinations to durably treat ER mutant cancer. To accomplish these goals, we will generate cell line models into which ER mutants have been knocked-in and patient derived organoid and xenograft models. We will evaluate existing ER antagonists and develop novel inhibitors to identify compounds that potently inhibit various ER mutants. Finally, we will use in vitro screens and tumor biopsies to characterize likely mechanisms of resistance to newer ER antagonists and nominate pharmacologic strategies to overcome these.

靶向雌激素受体（ER）治疗乳腺癌的药物已经非常成功