Defining mechanisms of resistance to hormonal therapy in breast cancer

乳腺癌激素治疗耐药机制的定义

• 批准号: 10304866
• 负责人: Sarat Chandarlapaty
• 金额: $ 40.26万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-05 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304866
• 关键词: Antiestrogen Therapy; Biopsy; Blood; Breast Cancer Patient; Breast Cancer Treatment; Cell Line; Clinical; Data; Disease; Disease Progression; Drug resistance; ERBB2 gene; ESR1 gene; Engineering; Epidermal Growth Factor Receptor; Estrogen Receptors; Estrogen receptor positive; Evolution; FRAP1 gene; Fulvestrant; Funding; Future; Genetic Transcription; Genomics; Goals; Hormonal; Ligand Binding Domain; MAP Kinase Gene; MEKs; Maps; Mediating; Metastatic breast cancer; Methodology; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Profiling; Monitor; Mutation; NF1 gene; NF1 mutation; PI3K/AKT; Pathway interactions; Patients; Population; Pre-Clinical Model; Receptor Gene; Recording of previous events; Recurrence; Resistance; Sampling; Selection for Treatments; Signal Transduction; Specimen; Therapeutic; Therapeutic Agents; Time; Work; base; cell free DNA; co-clinical trial; cohort; combinatorial; drug sensitivity; hormone therapy; inhibitor; insight; kinase inhibitor; malignant breast neoplasm; mutant; next generation sequencing; novel therapeutic intervention; patient derived xenograft model; patient response; pressure; prevent; prospective; resistance mechanism; response; targeted sequencing; therapy resistant; treatment response; tumor; tumor progression

ABSTRACT Hormonal therapy remains a mainstay of systemic treatment for the 70% of breast cancers that express the estrogen receptor (ER), but responses vary and intrinsic and acquired resistance are major clinical challenges. Recently, ligand-binding domain mutations in the estrogen receptor (ER) gene (ESR1) were found to occur and to mediate hormonal therapy resistance in approximately 35% of ER-positive (ER+) breast cancer patients. In the remaining two-thirds of cases, the molecular basis of hormonal therapy resistance is largely unknown. In preliminary data, based on targeted sequencing of 1756 breast cancer patients with recurrent or metastatic disease, we identified enrichment for alterations in diverse effectors of MAP kinase signaling (ERBB2 mutation, EGFR amplification, NF1 mutation, and others) in ESR1-wildtype breast cancers collected after disease progression on anti-estrogen therapy. This proposal is based on the hypothesis that recent advances in sequencing methodology and analysis of cell-free DNA (cfDNA) can prospectively identify molecular alterations that confer resistance to hormonal therapy in patients with breast cancer and that co-targeting such alterations alongside ER could prevent or delay the emergence of drug-resistant clones. Three specific aims are proposed. In Aim 1, paired tumor samples and cfDNA collected from breast cancer patients before and during treatment and at the time of disease progression on hormonal therapy will be used to define the landscape and timing of molecular changes that arise under the selective pressure of therapy. Our preliminary data indicate that ERBB2 mutation is a mechanism of both intrinsic and acquired resistance to hormonal therapy. We have also found that the HER kinase inhibitor neratinib can induce profound therapeutic responses that are limited by the induction of ER activity and consequent emergence of drug resistance. Thus, in Aim 2, we will use paired pretreatment and disease-progression tumor biopsies, cfDNA collected at regular intervals during treatment with neratinib alone or with the ER degrader fulvestrant, and engineered isogenic models and patient-derived xenografts to identify and validate mechanisms of resistance to these therapeutic agents. Finally, our genomic analysis identified RAS/ERK pathway alterations in ~10% of tumors collected following disease progression on hormonal therapy. In Aim 3, we will explore the functional significance of this finding and seek to develop therapeutic strategies for overcoming hormonal therapy resistance in this molecularly defined population. The long-term objective of this project is to develop therapeutic strategies for ER+ breast cancer guided by real-time, non-invasive molecular monitoring of tumor evolution. The work proposed will also generate valuable preclinical models of HER2-mutant and NF1-mutant ER+ breast cancer that can be used in future studies to assess promising novel therapeutic approaches for these molecularly defined populations.

抽象的 激素疗法仍然是 70% 乳腺癌全身治疗的支柱 雌激素受体（ER），但反应各不相同，内在和获得性耐药是主要的临床挑战。 最近，发现雌激素受体（ER）基因（ESR1）中的配体结合域发生突变， 介导约 35% ER 阳性 (ER+) 乳腺癌患者的激素治疗耐药性。在 其余三分之二的病例，激素治疗耐药的分子基础很大程度上未知。在 初步数据，基于对 1756 名复发或转移性乳腺癌患者进行的靶向测序 疾病中，我们发现了 MAP 激酶信号传导的不同效应器（ERBB2 突变、 病后收集的 ESR1 野生型乳腺癌中的 EGFR 扩增、NF1 突变等 抗雌激素治疗的进展。该提议基于以下假设： 测序方法和游离 DNA (cfDNA) 分析可以前瞻性地识别分子改变 赋予乳腺癌患者对激素治疗的抵抗力，并共同针对此类改变 与 ER 一起可以预防或延缓耐药克隆的出现。三个具体目标是 建议的。在目标 1 中，配对肿瘤样本和 cfDNA 从乳腺癌患者之前和期间收集 治疗和疾病进展时的激素治疗将用于定义景观和 在治疗的选择性压力下出现的分子变化的时间。我们的初步数据表明 ERBB2 突变是对激素治疗的内在和获得性耐药的机制。我们有 还发现 HER 激酶抑制剂 neratinib 可以引发有限的深度治疗反应 通过诱导 ER 活性并随后出现耐药性。因此，在目标 2 中，我们将使用 配对预处理和疾病进展肿瘤活检，期间定期收集 cfDNA 单独使用来那替尼或与 ER 降解剂氟维司群一起治疗，以及工程化的同基因模型和 患者来源的异种移植物，以识别和验证对这些治疗药物的耐药机制。 最后，我们的基因组分析确定了以下收集的约 10% 的肿瘤中 RAS/ERK 通路的改变 激素治疗的疾病进展。在目标 3 中，我们将探讨这一发现的功能意义 并寻求制定克服激素治疗耐药性的治疗策略 定义的人口。该项目的长期目标是开发 ER+ 乳腺的治疗策略 通过对肿瘤演变的实时、非侵入性分子监测来指导癌症。拟议的工作还将 生成有价值的 HER2 突变和 NF1 突变 ER+ 乳腺癌临床前模型，可用于 未来的研究将评估针对这些分子定义人群的有前景的新型治疗方法。