Therapeutic approaches to ER mutant breast cancer

ER突变乳腺癌的治疗方法

• 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
• 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

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)的药物在以下方面非常成功 然而，对于许多患者来说，控制疾病的获得性耐药性是经常遇到的。我们 在ER的配体结合域(LBD)中发现了高比例的反复突变 有这种获得性抵抗力的患者。我们发现，两种最常见的突变会促进 激动剂构象，尽管没有配体，但对芳香酶抑制剂(AI)产生抗药性， 与不良的临床结果相关，并可能成为某些ER拮抗剂的靶点。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，在那里 是不同突变体改变内质网功能的机制的多样性以及 不同突变对内质网构象和活性的影响这个项目的总体假设是 不同的ER LBD突变具有促进某种程度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潜力 抵抗。在这个提案中，我们将建立不同ESR1突变的机制 促进内质网活性，表征由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 抵抗ER突变疾病中的ER拮抗剂，并开发合理的组合来持久治疗 呃突变的癌症。为了实现这些目标，我们将生成ER突变体进入的细胞系模型 已有敲入和病人衍生的器官和异种移植模型。我们将评估现有的ER 拮抗剂，并开发新的抑制剂，以确定有效抑制各种ER突变体的化合物。 最后，我们将使用体外筛查和肿瘤活检来表征可能的耐药机制。 寻找更新的ER拮抗剂，并提出克服这些问题的药物策略。