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Mechanisms of estrogen receptor ligand signaling

雌激素受体配体信号传导机制

基本信息

批准号：
10681785
负责人：
Kendall W Nettles
金额：
$ 46.34万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-24 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10681785
关键词：
Address Agonist Aromatase Inhibitors Binding Biological Markers Biology Breast Cancer Cell Breast Cancer therapy Cell Nucleus Cells ChIP-seq Charcoal Chemicals Clinical Code Confocal Microscopy Disease Endocrine Enzymes Epidermal Growth Factor Receptor Estradiol Estrogen Receptors Estrogen receptor positive Fulvestrant Gene Expression Genes Genetic Transcription Goals Growth Growth Factor Growth Factor Receptors Histones Ligands MAP Kinase Gene Mediating Modality Modeling Molecular Molecular Conformation PIK3CG gene Pathway interactions Patients Postmenopause Premenopause Proliferating Proteins Proteomics Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation Resistance Selective Estrogen Receptor Modulators Signal Pathway Signal Transduction Tamoxifen Testing Transcriptional Regulation Western Blotting Woman antagonist bone cell growth effective therapy gene network gene repression genetic corepressor hormone therapy in vivo inhibitor malignant breast neoplasm novel therapeutics overexpression prevent receptor response scaffold targeted cancer therapy targeted treatment tool transcription factor

项目摘要

The estrogen receptor- (ER) represents one of the most successful molecular entities as both a biomarker and target for cancer therapy, but some 30-50% of patients show de novo or acquired resistance. ER is a ligand regulated transcription factor that acts as a scaffold for histone modifying enzymes to modulate gene expression and growth of ER+ breast cancers (BCs). Importantly, the different treatment modalities of SERMs, SERDs and aromatase inhibitors induce different conformational effects on ER that often allow resistance to one type of treatment to be effectively treated by another. There is currently a significant unmet clinical need for new therapies that are effective in de novo and acquired resistance models, such as overexpression of receptor tyrosine kinases or activation of their downstream signaling pathways. We recently showed that an EGFR overexpression model rendered breast cancer cells broadly resistant to SERMs, as seen in patients. We also developed a new chemical targeting strategy for ER, which we call dual mechanism ER inhibitors (DMERI). Importantly, we identified both SERM and SERD DMERI as efficacious in the EGFR overexpression model, and many of them showed efficacy greater than fulvestrant, and in fulvestrant resistance models. The SERM DMERI may be an effective treatment for patients with EGFR overexpression at initial presentation, comprising a significant subset of ER+ BCs associated with clinical resistance. The marked difference in efficacy between SERMs and SERM DMERI in this resistant model provide us with robust chemical biology tools to dissect mechanisms of action. Our first goal is to understand the mechanisms of ER/EGFR signaling crosstalk and its regulation by different classes of ER ligands. A second goal is to understand the molecular mechanisms of ligand efficacy more generally through identifying ligand-specific coregulator- gene networks that regulate ER-dependent growth inhibition. The delineation of the ligand-receptor-coregulator gene code will enable understanding ligand mechanism of action and basic principles of transcription regulation in control of cell growth.

雌激素受体（ER）是最成功的分子实体之一，作为生物标志物和靶标