Functional Characterization and Clinical Prevalence of ESR1 Fusions in Advanced Endocrine Resistant Breast Cancer

晚期内分泌耐药乳腺癌中 ESR1 融合的功能特征和临床患病率

基本信息

批准号：
10368929
负责人：
Megan Yates
金额：
$ 4.79万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10368929
关键词：
Aromatase Inhibitors Binding Biological Markers Biology Biopsy Specimen Blood Blood specimen Breast Cancer Cell Breast Cancer Detection Breast Cancer Model Breast Cancer Patient Breast Cancer cell line Cancer Cell Growth Cancer Etiology Cancer Prognosis Candidate Disease Gene Cell Line Cell Proliferation Cells Cessation of life ChIP-seq Chimeric Proteins Clinical Clinical Management Collection Controlled Clinical Trials DNA Sequence Alteration Data Detection Development Diagnosis Dimerization Disease Disease Progression ESR1 gene Endocrine Estrogen Antagonists Estrogen Receptors Estrogen Therapy Estrogen receptor positive Estrogens Event Exhibits Female Gene Fusion Genes Genetic Transcription Genomics Goals Growth Hormonal Human In Vitro Investigation Lead Ligand Binding Domain Ligands Lung Malignant - descriptor Malignant Neoplasms Medicine Metastatic breast cancer Metastatic to Modality Modeling Molecular Monitor Monitoring Clinical Trials Mutagenesis Mutation Nature Neoplasm Metastasis Outcome Pathway interactions Patients Persons Phase II Clinical Trials Phenotype Point Mutation Prevalence Prevalence Study Progression-Free Survivals Property RNA Randomized Recurrence Refractory Disease Regimen Relapse Research Personnel Resistance Resistance development Risk Role Sampling Selective Estrogen Receptor Modulators Signal Pathway Signal Transduction Structure-Activity Relationship Survival Rate Techniques Training Translational Research Treatment Protocols Woman advanced breast cancer alternative treatment breast cancer diagnosis cell growth clinically relevant clinically significant exosome fusion gene gene product gene translocation hormone therapy improved in vitro testing in vivo innovation liquid biopsy malignant breast neoplasm metastatic process migration mortality novel patient derived xenograft model receptor response screening stem therapy development therapy resistant transcription factor transcriptome transcriptome sequencing treatment strategy tumor tumor progression

项目摘要

PROJECT SUMMARY Breast cancer (BrCa) is the second leading cause of cancer related deaths in women and the majority of mortality is due to metastatic BrCa disease. Although our understanding and treatment of advanced breast cancer has improved, the 5-year survival rate remains at a dismal 22%. Two-thirds of all BrCa is positive for estrogen receptor (ESR1, ER), which can be exploited by targeted anti-estrogen therapeutics. Unfortunately, 25% of ER-positive primary disease patients and nearly all ER-positive metastatic BrCa patients will go on to develop treatment refractory disease to these targeted regimens. ER is a prominent component of cancer progression; thus, it is imperative to understand how advance ER-positive patients confer treatment resistance. The Lee-Oesterreich lab recently discovered a novel genomic alternation to ESR1, an in-frame translocation event creating a fusion gene product. A subsequent panel of ESR1 fusions have been discovered and these ESR1 fusions are estimated to be prevalent in at least 1-5% of advanced ER-positive BrCa disease. Importantly, these fusions were identified in patients who developed resistance to hormonal therapy. The functional role of these genomic fusion genes requires further investigation. We will investigate how ESR1 fusions influence cellular proliferation, treatment insensitivity and migration/invasion. Our preliminary data of a fusion stably expressed in a BrCa cell line exhibited enhanced growth and lack of response to hormonal treatment. We will also analyze transcriptional and mechanistic changes invoked by ESR1 fusion expression. Preliminary data of ESR1 fusions transiently transfected into a BrCa cell line exhibited enhanced ER activation compared to parental and wildtype ER expressing cells. Direct mutagenesis of the fusion partner will better elucidate the contribution of ESR1 or the fusion partner to global cellular changes. Lastly, we will study the prevalence of the fusion genes in metastatic refractory disease to determine clinical significance. We will analyze exosomal RNA isolated from patient blood draws to detect presence of known and novel fusions. This proposal will ultimately 1) better analyze the metastatic properties of ESR1 fusions both in the presence and absence of treatment, 2) gain a greater appreciation of ESR1 fusion influence on the transcriptome and cistrome and lastly 3) define fusion prevalence in advance BrCa and detection of novel fusions over the course of a controlled clinical trial utilizing anti-estrogen treatment. Successful completion of these Aims will help inform clinicians and researchers the clinical relevance of ESR1 fusions and if these genomic alternations can serve as biomarkers for identifying treatment resistant breast cancer and rationale for alternative treatment strategies.

项目概要乳腺癌 (BrCa) 是女性癌症相关死亡的第二大原因，大多数女性死亡是由于转移性 BrCa 疾病所致。虽然我们对晚期乳腺的认识和治疗癌症有所改善，但 5 年生存率仍仅为 22%。三分之二的 BrCa 呈阳性雌激素受体（ESR1、ER），可用于靶向抗雌激素治疗。很遗憾， 25% 的 ER 阳性原发性疾病患者和几乎所有 ER 阳性转移性 BrCa 患者将继续接受治疗针对这些靶向治疗方案制定难治性疾病的治疗方案。 ER 是癌症的一个重要组成部分进展；因此，必须了解晚期 ER 阳性患者如何产生治疗抵抗。 Lee-Oesterreich 实验室最近发现了 ESR1 的一种新的基因组改变，即框内易位创建融合基因产品的事件。随后发现了一组 ESR1 融合体，并且这些据估计，ESR1 融合在至少 1-5% 的晚期 ER 阳性 BrCa 疾病中普遍存在。重要的是，这些融合是在对激素治疗产生耐药性的患者中发现的。这些基因组融合基因的功能作用需要进一步研究。我们将研究 ESR1 如何融合影响细胞增殖、治疗不敏感性和迁移/侵袭。我们的初步数据在 BrCa 细胞系中稳定表达的融合蛋白表现出生长增强且缺乏对激素的反应治疗。我们还将分析 ESR1 融合表达引起的转录和机制变化。 ESR1融合体瞬时转染至BrCa细胞系的初步数据显示内质网激活增强与亲代和野生型 ER 表达细胞相比。融合伴侣直接诱变效果会更好阐明 ESR1 或融合伙伴对整体细胞变化的贡献。最后，我们将研究融合基因在转移性难治性疾病中的患病率以确定临床意义。我们将分析从患者抽血中分离的外泌体 RNA，以检测已知和新型融合的存在。该提案最终将 1) 更好地分析存在 ESR1 融合的转移特性和缺乏治疗，2) 更好地了解 ESR1 融合对转录组的影响， cistrome 和最后 3) 提前定义融合流行率 BrCa 并在整个过程中检测新的融合利用抗雌激素治疗的对照临床试验。成功完成这些目标将有助于告知临床医生和研究人员 ESR1 融合的临床相关性以及这些基因组改变是否可以作为识别治疗耐药性乳腺癌的生物标志物和替代治疗的理由策略。