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.

项目摘要乳腺癌（BRCA）是妇女癌症与癌症相关的第二大原因，大多数是死亡率是由于转移性BRCA疾病引起的。尽管我们对高级乳房的理解和治疗癌症有所改善，5年的存活率仍处于令人沮丧的22％。所有BRCA的三分之二对雌激素受体（ESR1，ER），可以通过靶向抗雌激素疗法来利用。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患者将继续进行为这些靶向方案发展治疗难治性疾病。 ER是癌症的重要组成部分进展；因此，必须了解前进的ER阳性患者如何赋予治疗性耐药性。 Lee-Oesterreich实验室最近发现了一种与ESR1的新型基因组交替，ESR1是一个框架内易位事件创建融合基因产品。随后发现了ESR1融合面板，这些 ESR1融合估计在至少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疗法抗性的患者中鉴定出来的。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 融合会影响细胞增殖，治疗不敏感和迁移/侵袭。我们的初步数据在BRCA细胞系中稳定表达的融合表现出增长的增长和对激素的反应治疗。我们还将分析ESR1融合表达引用的转录和机械变化。 ESR1融合的初步数据瞬时转染到BRCA细胞系中表现出增强的ER激活与父母和野外表达细胞相比。融合合作伙伴的直接诱变会更好阐明ESR1或融合伴侣对全球细胞变化的贡献。最后，我们将研究融合基因转移性难治性疾病中融合基因的患病率确定临床意义。我们将分析从患者血液中分离出来的外泌体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ESR1融合的转移性特性以及缺乏治疗，2）对ESR1融合对转录组的影响更大的理解和 cistrome和最后3）提前定义了融合率，并且在整个过程中发现了新型融合利用抗雌激素治疗的对照临床试验。这些目标成功完成将有助于告知临床医生和研究人员ESR1融合的临床相关性，如果这些基因组交替可以用作鉴定耐药性乳腺癌和替代治疗的生物标志物策略。