Project 1: Targeting HSPA Proteins in Advanced and Recurrent Endometrial Cancer Therapy

项目 1:针对晚期和复发性子宫内膜癌治疗中的 HSPA 蛋白

基本信息

  • 批准号:
    10711636
  • 负责人:
  • 金额:
    $ 40.34万
  • 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:
    2023-08-23 至 2028-07-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY The incidence and mortality of endometrial cancer has increased over the past few decades, and is predicted to continue rising. There is significant need for improved therapies with reduced toxicity for women with endometrial cancers that are advanced, recurrent or refractory to standard of care. Endometrial cancer is a heterogeneous disease that has been classified into molecular profile categories with different degrees of patient prognosis. Across these categories, endometrial cancer has the highest rates of mutations in heat shock protein A(HSPA) 5, 8 and 9 genes compared to other The Cancer Genome Atlas-studied cancers. The HSPA5, HSPA8 and HSPA9 genes encode chaperone proteins, Grp78, hsc70 and mortalin, respectively, which become elevated during carcinogenesis to bind and modulate oncoproteins in a way that assures cancer cell survival. Thus, these chaperone/oncoprotein complexes represent differential targets present at higher levels in cancer cells compared to healthy cells. We developed a drug, SHetA2 (NSC 726189), which disrupts these complexes. SHetA2 induces growth arrest, altered metabolism, mitophagy and cell death in endometrial cancer cells, while the effects on healthy cells is limited to G1 cell cycle arrest. Preclinical studies found lack of SHetA2 toxicity, and this drug is now in a Phase 1 clinical trial in advanced, recurrent or persistent gynecologic cancers (NCT04928508). In vivo studies revealed that SHetA2 has complementary activities and efficacies with paclitaxel and cyclin dependent kinase (CDK4/6) inhibitors. In this project, we hypothesize that SHetA2 will safely reduce endometrial cancer tumor burden and complement the efficacies of paclitaxel and CDK4/6 inhibitors without increasing toxicity; the mechanism will be mediated through SHetA2 disruption of HSPA/client protein complexes; and the treatment efficacies will be modulated by mutations in PTEN and TP53 genes. To test this, and optimize SHetA2-based therapies, we propose to study the mechanism of SHetA2 in healthy endometrial cells, endometrial cancer cell lines, and patient derived organoids and xenografts with a range of natural or induced genetic mutations in PTEN and TP53 genes. We will conduct a Phase 1 clinical trial of SHetA2 in combination with paclitaxel in advanced, recurrent or persistent endometrial cancer patients; a Phase 2 expansion will evaluate response. Using specimens from this and other trials, we will test the hypothesis that mortalin co-localization with the Mps1 kinase or p53 at the centrosome correlates with poor or improved response, respectively, of paclitaxel-treated endometrial cancer patients. In preparation for a future clinical trial, we will use a quantitative systems biology approach that integrates pharmacokinetic, pharmacodynamic and toxicity data to optimize dose and schedule for testing SHetA2 in combination with CDK4/6 inhibitors. The outcome is anticipated to identify biomarkers predictive of which patients will most likely benefit from SHetA2- based therapies, and provide justification and data for development of a randomized Phase 3 trial of a SHetA2 combination anticipated to have an improved therapeutic window over current therapy.
项目总结

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 }}

DORIS Mangiaracina BENBROOK其他文献

DORIS Mangiaracina BENBROOK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 }}

{{ truncateString('DORIS Mangiaracina BENBROOK', 18)}}的其他基金

Route 66 Endometrial Cancer SPORE
66 号公路子宫内膜癌孢子
  • 批准号:
    10711634
  • 财政年份:
    2023
  • 资助金额:
    $ 40.34万
  • 项目类别:
Gynecologic Cancers Research Program
妇科癌症研究计划
  • 批准号:
    10177891
  • 财政年份:
    2018
  • 资助金额:
    $ 40.34万
  • 项目类别:
Gynecologic Cancers Research Program
妇科癌症研究计划
  • 批准号:
    10413078
  • 财政年份:
    2018
  • 资助金额:
    $ 40.34万
  • 项目类别:
Targeting HPV Consequences in a Cervical Cancer Clinical Trial
在宫颈癌临床试验中针对 HPV 后果
  • 批准号:
    9052455
  • 财政年份:
    2016
  • 资助金额:
    $ 40.34万
  • 项目类别:
Targeting HPV Consequences in a Cervical Cancer Clinical Trial
在宫颈癌临床试验中针对 HPV 后果
  • 批准号:
    9492554
  • 财政年份:
    2016
  • 资助金额:
    $ 40.34万
  • 项目类别:
Targeting HPV Consequences in a Cervical Cancer Clinical Trial
在宫颈癌临床试验中针对 HPV 后果
  • 批准号:
    10163132
  • 财政年份:
    2016
  • 资助金额:
    $ 40.34万
  • 项目类别:
Ovarian Cancer Chemoprevention
卵巢癌化学预防
  • 批准号:
    9316591
  • 财政年份:
    2015
  • 资助金额:
    $ 40.34万
  • 项目类别:
Ovarian Cancer Chemoprevention
卵巢癌化学预防
  • 批准号:
    9093746
  • 财政年份:
    2015
  • 资助金额:
    $ 40.34万
  • 项目类别:
Ovarian Cancer Chemoprevention
卵巢癌化学预防
  • 批准号:
    8986266
  • 财政年份:
    2015
  • 资助金额:
    $ 40.34万
  • 项目类别:
Mechanism of SHeA2 Action in Ovarian Cancer
SHeA2 在卵巢癌中的作用机制
  • 批准号:
    7609055
  • 财政年份:
    2005
  • 资助金额:
    $ 40.34万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了