Structural-Transcriptional Relationships that Improve Y537S Estrogen Receptor Antagonism

改善 Y537S 雌激素受体拮抗作用的结构转录关系

基本信息

  • 批准号:
    10636229
  • 负责人:
  • 金额:
    $ 35.79万
  • 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:
    2023-05-11 至 2028-04-30
  • 项目状态:
    未结题

项目摘要

Summary This proposal studies how drug-induced structural changes to Y537S estrogen receptor alpha (ERα) impact anti- tumoral activities in hormone-resistant breast cancer cells. Breast cancer is the second leading cause of cancer death in the United States. Acquired resistance to hormone therapies is a leading contributor to mortality. In approximately 40% of progressive ER+ patients, prolonged selective pressure by antiestrogenic therapies gives raise to tumors bearing activating somatic ESR1 (the gene for ERα) mutations. These mutations resist inhibition by clinically approved hormone therapies and engage new transcriptional programs that boost metastatic potential. Y537S missense mutation is among the most common and enables the greatest hormone-free transcriptional activities and resistance to antiestrogen. Next generation selective estrogen receptor degraders (SERDs) have been clinically deployed to address this mechanism of drug resistance. However, they show variable activities in Y537S ESR1 breast cancers and possess common side-effects that will limit their long-term use. We recently studied how a panel of 17 selective estrogen receptor modulators (SERMs) and SERDs bind to and affect Y537S ERα activities in breast cancer cells. We identified structurally distinct SERMs and SERDs with improved activities in this setting. While structurally distinct, our x-ray co-crystal structures showed that the most effective molecules engaged the same S537-E380 hydrogen bond to reinforce the therapeutic antagonist conformation. Therefore, we hypothesize that novel ligand-dependent structural interactions will improve therapeutic antagonistic activities in the Y537S ESR1 setting. In this study, we will leverage our library of over 100 diverse SERMs and SERDs to reveal the structural-transcriptional relationships that underlie improved anti- cancer activities Y537S ESR1 breast cancer cells. We will start by studying how our library binds to and affects Y537S ERα structure and anti-cancer activities (Aim 1). This approach will reveal the ligand binding modes and structural interactions that enable potency. Next, we will study how the most effective molecules impact Y537S ERα genomic activities including protein-protein interactions, genome binding, and transcriptional programing (Aim 2). This approach will show whether the efficacies of SERMs and SERDs arise from alterations to Y537S ERα genomic activities. Finally, we will reveal the anti-tumor and tissue-specific activities of the most effective SERMs and SERDs in hormone-resistant ER+ breast cancer in vivo (Aim 3). This approach will reveal whether our in vitro observations correspond to improved anti-cancer activities in patient-relevant tumor models. Overall, these studies will provide detailed structural-transcriptional relationships to improve therapeutic targeting of Y537S ERα in hormone-resistant breast cancer.
总结

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Sean William Fanning其他文献

Sean William Fanning的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

相似海外基金

How novices write code: discovering best practices and how they can be adopted
新手如何编写代码:发现最佳实践以及如何采用它们
  • 批准号:
    2315783
  • 财政年份:
    2023
  • 资助金额:
    $ 35.79万
  • 项目类别:
    Standard Grant
One or Several Mothers: The Adopted Child as Critical and Clinical Subject
一位或多位母亲:收养的孩子作为关键和临床对象
  • 批准号:
    2719534
  • 财政年份:
    2022
  • 资助金额:
    $ 35.79万
  • 项目类别:
    Studentship
A material investigation of the ceramic shards excavated from the Omuro Ninsei kiln site: Production techniques adopted by Nonomura Ninsei.
对大室仁清窑遗址出土的陶瓷碎片进行材质调查:野野村仁清采用的生产技术。
  • 批准号:
    20K01113
  • 财政年份:
    2020
  • 资助金额:
    $ 35.79万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
  • 批准号:
    2633211
  • 财政年份:
    2020
  • 资助金额:
    $ 35.79万
  • 项目类别:
    Studentship
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
  • 批准号:
    2436895
  • 财政年份:
    2020
  • 资助金额:
    $ 35.79万
  • 项目类别:
    Studentship
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
  • 批准号:
    2633207
  • 财政年份:
    2020
  • 资助金额:
    $ 35.79万
  • 项目类别:
    Studentship
A Study on Mutual Funds Adopted for Individual Defined Contribution Pension Plans
个人设定缴存养老金计划采用共同基金的研究
  • 批准号:
    19K01745
  • 财政年份:
    2019
  • 资助金额:
    $ 35.79万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The limits of development: State structural policy, comparing systems adopted in two European mountain regions (1945-1989)
发展的限制:国家结构政策,比较欧洲两个山区采用的制度(1945-1989)
  • 批准号:
    426559561
  • 财政年份:
    2019
  • 资助金额:
    $ 35.79万
  • 项目类别:
    Research Grants
Securing a Sense of Safety for Adopted Children in Middle Childhood
确保被收养儿童的中期安全感
  • 批准号:
    2236701
  • 财政年份:
    2019
  • 资助金额:
    $ 35.79万
  • 项目类别:
    Studentship
Structural and functional analyses of a bacterial protein translocation domain that has adopted diverse pathogenic effector functions within host cells
对宿主细胞内采用多种致病效应功能的细菌蛋白易位结构域进行结构和功能分析
  • 批准号:
    415543446
  • 财政年份:
    2019
  • 资助金额:
    $ 35.79万
  • 项目类别:
    Research Fellowships
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了