Mechanisms of estrogen receptor ligand signaling

雌激素受体配体信号传导机制

• 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
• 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

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-α (ER) 代表了最成功的分子实体之一，作为生物标志物和靶点 癌症治疗，但约 30-50% 的患者表现出新的或获得性耐药性。 ER是配体调节的转录 作为组蛋白修饰酶支架调节 ER+ 乳腺癌基因表达和生长的因子 （BC）。重要的是，SERM、SERD 和芳香酶抑制剂的不同治疗方式会导致不同的治疗效果。 对 ER 的构象影响通常使得对一种治疗的耐药性可以被另一种治疗有效地治疗。那里 目前对新疗法的重大未满足的临床需求是对从头和获得性耐药模型有效的新疗法， 例如受体酪氨酸激酶的过度表达或下游信号通路的激活。我们最近 研究表明，EGFR 过表达模型使乳腺癌细胞对 SERM 具有广泛的耐药性，正如在患者中所见。 我们还开发了一种新的 ER 化学靶向策略，我们称之为双机制 ER 抑制剂 (DMERI)。 重要的是，我们确定 SERM 和 SERD DMERI 在 EGFR 过表达模型中均有效，并且许多 它们在氟维司群耐药模型中的疗效优于氟维司群。 SERM DMERI 可能是一种有效的 针对初次就诊时 EGFR 过度表达的患者（包括 ER+ BC 的重要子集）的治疗 与临床耐药性有关。 SERM 和 SERM DMERI 治疗这种耐药性的疗效存在显着差异 模型为我们提供了强大的化学生物学工具来剖析作用机制。我们的首要目标是了解 ER/EGFR 信号串扰的机制及其不同类别 ER 配体的调节。第二个目标是 通过识别配体特异性共调节剂，更广泛地了解配体功效的分子机制 调节 ER 依赖性生长抑制的基因网络。配体-受体-共调节基因密码的描述 将有助于理解配体的作用机制和控制细胞的转录调控的基本原理 生长。