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Estrogen receptor fusions genes as drivers of endocrine resistance in breast cancer

雌激素受体融合基因作为乳腺癌内分泌抵抗的驱动因素

基本信息

批准号：
10373094
负责人：
Adrian V Lee
金额：
$ 56.59万
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：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10373094
关键词：
Adopted Amino Acids Antiestrogen Therapy Base Pairing Binding Biological Assay Biology Biopsy Breast Cancer Model Breast Cancer cell line Breast Cancer therapy C-terminal Cell Line Cell model Cells Clinical Code Collection DNA Binding Data Detection Development Disease Drug Modelings Drug resistance ESR1 gene Endocrine Engineering Estrogen Antagonists Estrogen Receptors Estrogen Therapy Estrogen receptor positive Estrogens Evolution Exons Gene Expression Gene Fusion Gene Rearrangement Genes Genetic Transcription Genomics Goals Histologic Hormones Hyperactivity International Introns Ligand Binding Ligands MDA MB 435 Malignant Neoplasms Mediator of activation protein Messenger RNA Metastatic breast cancer Missense Mutation Molecular Molecular Conformation Monitor Mutation N-terminal Organoids Pathway interactions Patients Plasma Point Mutation Prevalence Prevention Promoter Regions Proteins Recurrence Reporting Resistance Role Solid Neoplasm Structural Biologist Structure Testing Therapeutic Intervention Transactivation Translating Xenograft Model Xenograft procedure advanced breast cancer advanced disease biophysical techniques clinically relevant cohort fusion gene gain of function genome sequencing genomic data genomic locus hormone therapy in vivo insight malignant breast neoplasm mortality multidisciplinary novel novel therapeutics patient derived xenograft model promoter response tumor tumor DNA whole genome

项目摘要

Anti-estrogen therapy is key to the prevention and treatment of estrogen receptor (ER, ESR1) positive breast cancer, but therapy resistance occurs in up to a half of cases resulting in incurable advanced disease. We recently reported recurrent ESR1 fusions in advanced endocrine-resistant breast cancers, with loss of ligand binding representing a canonical model of drug resistance. Intriguingly, cases with ESR1 fusions co-occurred with ESR1 base-pair mutations, likely pointing towards convergent evolution under prolonged anti-estrogen therapy. Evidence from our group and others suggest that ESR1 fusions are found in ~10-20% of advanced breast cancers, however, many ESR1 fusions harbor different 3’ partner genes, making detection challenging. To determine prevalence, we will comprehensively re-analyze the ESR1 genomic locus in data from metastatic breast cancers. Further, we have developed and optimized a target capture sequencing assay capable of comprehensively detecting ESR1 fusions in both tumor biopsies and ctDNA. We have identified endogenous ESR1 fusions that are expressed in two patient derived xenografts (PDX) (ESR1-LPP and ESR1-NFkB) and in an ER-positive breast cancer cell line MDA-MB-435 (ESR1-SYNE1). We will express ESR1 fusions in recently generated patient-derived organoids (PDO) which show ER expression and response to estrogen that is equal or greater than traditional cell lines. Intriguingly, different ESR1 fusions show stark differences in activity, implicating a role for the 3’ gene partner in modulating activity of the ESR1 N terminal domain (NTD). The NTD is an intrinsically disordered protein within the transactivation domain, and using a novel integrative-biophysics approach, we recently reported that while it is mostly disordered, it can adopt an unexpectedly compact conformation which in turn directs interaction with coregulators. In this proposal we seek to test the hypothesis that ESR1 fusions are key mediators of endocrine-resistance and breast cancer mortality. We will employ EnRich to determine the prevalence of ESR1 fusions (and point mutations) in national and international clinical cohorts of advanced endocrine resistant breast cancer and monitor when they arise during therapy using longitudinal collection of plasma and ctDNA analyses. We will use patient-derived organoid models of breast cancer to compare and contrast the activity and function of ESR1 fusions and point mutations relative to wild- type ER and translate this into in vivo patient derived organoid xenograft (PDOX) and (PDX) models to assess endocrine resistance. We will study mechanism of action, including the effects on DNA binding and transcriptional activity, and the role of the 3’ partner gene in any gain of function activities. Finally, we will examine the structure-function of ESR1 fusions focusing on the NTD and determining the altered structure in the context of the fusion partner before assessing the function of specific NTD amino acids and how they change structure and subsequent target gene expression. We believe our multi-disciplinary studies will provide mechanistic insight to aid in the development of new therapies against breast cancers with ESR1 fusions.

抗雌激素治疗是预防和治疗雌激素受体（ER, ESR1）阳性乳腺的关键