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:
- 金额:$ 46.34万
- 依托单位:
- 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:
- 关键词:AddressAgonistAromatase InhibitorsBindingBiological MarkersBiologyBreast Cancer CellBreast Cancer therapyCell NucleusCellsChIP-seqCharcoalChemicalsClinicalCodeConfocal MicroscopyDiseaseEndocrineEnzymesEpidermal Growth Factor ReceptorEstradiolEstrogen ReceptorsEstrogen receptor positiveFulvestrantGene ExpressionGenesGenetic TranscriptionGoalsGrowthGrowth FactorGrowth Factor ReceptorsHistonesLigandsMAP Kinase GeneMediatingModalityModelingMolecularMolecular ConformationPIK3CG genePathway interactionsPatientsPostmenopausePremenopauseProliferatingProteinsProteomicsReceptor Protein-Tyrosine KinasesReceptor SignalingRegulationResistanceSelective Estrogen Receptor ModulatorsSignal PathwaySignal TransductionTamoxifenTestingTranscriptional RegulationWestern BlottingWomanantagonistbonecell growtheffective therapygene networkgene repressiongenetic corepressorhormone therapyin vivoinhibitormalignant breast neoplasmnovel therapeuticsoverexpressionpreventreceptorresponsescaffoldtargeted cancer therapytargeted treatmenttooltranscription 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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Kendall W Nettles其他文献
Kendall W Nettles的其他文献
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{{ truncateString('Kendall W Nettles', 18)}}的其他基金
Estrogen receptor control of inflammatory gene expression
雌激素受体控制炎症基因表达
- 批准号:
9515944 - 财政年份:2017
- 资助金额:
$ 46.34万 - 项目类别:
Estrogen receptor control of inflammatory gene expression
雌激素受体控制炎症基因表达
- 批准号:
9290487 - 财政年份:2017
- 资助金额:
$ 46.34万 - 项目类别:
Structural features of the nuclear receptor signaling code
核受体信号编码的结构特征
- 批准号:
8345296 - 财政年份:2012
- 资助金额:
$ 46.34万 - 项目类别:
Structural features of the nuclear receptor signaling code
核受体信号编码的结构特征
- 批准号:
8535796 - 财政年份:2012
- 资助金额:
$ 46.34万 - 项目类别:
Structural features of the nuclear receptor signaling code
核受体信号编码的结构特征
- 批准号:
8727622 - 财政年份:2012
- 资助金额:
$ 46.34万 - 项目类别:
STRUCTURAL BASIS OF NUCLEAR HORMONE RECEPTOR LIGAND INTERACTIONS
核激素受体配体相互作用的结构基础
- 批准号:
7954316 - 财政年份:2009
- 资助金额:
$ 46.34万 - 项目类别:
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