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）代表最成功的分子实体之一，既是生物标志物，又是目标癌症治疗，但约30-50％的患者表现出从头或获得的抗药性。 ER是配体调节的转录用作组蛋白修饰酶以调节基因表达和ER+乳腺癌生长的脚手架的因素（BCS）。重要的是，Serm，SERDS和芳香酶抑制剂的不同处理方式会诱导不同对ER的构象作用通常允许对一种类型的治疗有效治疗另一种治疗。那里目前是对新疗法的重大未满足的临床需求，这些疗法在从头和获得的阻力模型中有效，例如受体酪氨酸激酶的过表达或其下游信号通路的激活。我们最近表明EGFR过表达模型使乳腺癌细胞广泛抗Serm，如患者所见。我们还为ER制定了一种新的化学靶向策略，我们称之为双重机制ER抑制剂（DMERI）。重要的是，我们在EGFR过表达模型中确定Serm和Serd Dmeri是有效的，许多它们显示出比Fulvestort的有效性，在Fulvestort抗性模型中。 Serm Dmeri可能是有效的在初次介绍时为EGFR过表达的患者进行治疗，完成了ER+ BC的大量子集与临床抵抗有关。 Serm和Serm Dmeri在这种抗性中的效率明显差异模型为我们提供了强大的化学生物学工具，以剖析作用机理。我们的第一个目标是了解 ER/EGFR信号传导串扰的机理及其对不同类别配体的调节。第二个目标是通过鉴定配体特异性核心调节剂，更普遍地了解配体效率的分子机制调节ER依赖性生长抑制的基因网络。配体受体调节器基因代码的描述将使能够理解控制细胞中的作用机理和转录调节的基本原理生长。