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.

针对乳腺癌雌激素受体 (ER) 的药物在治疗乳腺癌方面取得了巨大成功许多患者控制了该疾病，但经常遇到获得性耐药。我们已发现 ER 配体结合域 (LBD) 中的复发性突变占很高比例具有这种获得性耐药性的患者。我们发现两种最常见的突变促进尽管不存在配体，但仍具有激动剂构象，导致对芳香酶抑制剂（AI）的耐药性，与不良的临床结果相关，并且可能是某些 ER 拮抗剂的目标。然而，我们最近发现存在一系列临床 ESR1 突变。我们的数据显示，有是不同突变体改变 ER 功能的机制的多样性以及不同突变对 ER 构象和活性的影响。本项目的总体假设是不同的 ER LBD 突变具有促进一定水平的雌激素非依赖性的能力受体活性，但在驱动肿瘤表型和促进药物方面具有独特的效力反抗。在本提案中，我们将建立不同 ESR1 突变的机制促进 ER 活性，表征不同突变驱动的基因表达程序，了解不同突变对 ER 抑制敏感性的影响，确定可能的途径 ER突变性疾病中对ER拮抗剂的耐药性，并开发合理的组合来持久治疗 ER突变癌。为了实现这些目标，我们将生成细胞系模型，其中 ER 突变体已被敲入并源自患者的类器官和异种移植模型。我们将评估现有的 ER 拮抗剂并开发新型抑制剂来鉴定有效抑制各种 ER 突变体的化合物。最后，我们将使用体外筛选和肿瘤活检来表征可能的耐药机制寻找新的 ER 拮抗剂并指定药理学策略来克服这些问题。