Identifying Combination Therapies in Ovarian Tumors using High Throughput Dynamic BH3 Profiling

使用高通量动态 BH3 分析确定卵巢肿瘤的联合疗法

基本信息

  • 批准号:
    10307520
  • 负责人:
  • 金额:
    $ 6.98万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-12-01 至 2023-11-30
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract Ovarian cancer is the fifth leading cause of cancer deaths overall in women. The most recent estimates indicate that over 20,000 new cases will be diagnosed this year and nearly 14,000 women will die of the disease in the US in 2019 alone. The platinum-based standard of care cytotoxic regimen has remained largely stagnant for the last 15 years and recurrent disease is frequently platinum-resistant. Despite some recent success using molecular targeted agents and maintenance therapies (such as PARP inhibitors), the genetic complexity and lack of common molecular drivers make predicting patient responses difficult. Additionally, in relapsed patients, molecular changes induced by cancer therapies are multifaceted. Combining multiple drugs to treat ovarian cancer may be the most direct path to overcoming this intra-tumoral heterogeneity and acquired resistance to achieve more durable clinical responses. In an effort to capitalize on drugs that are approved and show patient benefit, this proposal seeks to identify compounds that can sensitize cells to apoptosis when combined with one of three drugs that act as cornerstones in ovarian cancer therapy: carboplatin, the PARP inhibitor olaparib, and doxorubicin. In the first aim a novel high-throughput screening platform called high-throughput dynamic BH3 profiling, will be used to identify whether a 24-hour ex vivo chemical treatment sensitizes tumor cells to mitochondrial mediated apoptosis. This will be performed using three ovarian cancer models: (1) freshly isolated tumor cells from primary patient ascites fluid, (2) organoid cultures derived from primary tumors, and (3) ovarian tumor cell lines. Preliminary data indicates that BH3 mimetics in combination with the standard of care drugs can increase apoptotic induction. In the second aim, the mechanism of drug-induced BH3 mimetic sensitivity will be investigated on the cellular, mitochondrial, and molecular level to determine which cellular contexts are likely to benefit from specific BH3 mimetic combinations. In the third and final aim compounds identified that increase apoptotic induction in combination with each of the three standard of care drugs will be tested in recently developed patient-derived luciferized tumor xenograft models of ovarian cancer. This will provide in vivo validation of the ability of specific drug combinations to cause tumor regression. This innovative approach offers both the potential to identify effective combinations to use in the platinum-sensitive, PARP-sensitive, and platinum-resistant settings, and the opportunity to determine molecular features that can identify populations that would benefit from these combinations. Supplementing the research component of the proposal with select courses and workshops, engagement in research meetings and seminars, and participation in scientific conferences will ensure an understanding of current concepts and techniques, constant feedback regarding the project's results and progress, and enhanced exposure to more translational work. Collectively, the research and training plan will provide a strong foundation upon which to build a career as a productive, independent cancer researcher.
项目总结/文摘

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 }}

Kelley McQueeney其他文献

Kelley McQueeney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('Kelley McQueeney', 18)}}的其他基金

Identifying Combination Therapies in Ovarian Tumors using High Throughput Dynamic BH3 Profiling
使用高通量动态 BH3 分析确定卵巢肿瘤的联合疗法
  • 批准号:
    10534744
  • 财政年份:
    2020
  • 资助金额:
    $ 6.98万
  • 项目类别:

相似海外基金

Development of decellularized small-diameter arterial grafts and evaluation in large animal experiments
脱细胞小直径动脉移植物的研制及大动物实验评价
  • 批准号:
    21H03016
  • 财政年份:
    2021
  • 资助金额:
    $ 6.98万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Developing and validating a computational model of the gut microbiota-mucosa interactions to replace and reduce animal experiments
开发和验证肠道微生物群-粘膜相互作用的计算模型,以取代和减少动物实验
  • 批准号:
    NC/R001707/1
  • 财政年份:
    2018
  • 资助金额:
    $ 6.98万
  • 项目类别:
    Training Grant
Developing and validating a computational model of the gut microbiota-mucosa interactions to replace and reduce animal experiments
开发和验证肠道微生物群-粘膜相互作用的计算模型,以取代和减少动物实验
  • 批准号:
    2103295
  • 财政年份:
    2018
  • 资助金额:
    $ 6.98万
  • 项目类别:
    Studentship
Research on the way of information transmission to gain social understanding of animal experiments
动物实验获得社会理解的信息传递方式研究
  • 批准号:
    16K07080
  • 财政年份:
    2016
  • 资助金额:
    $ 6.98万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
CDS&E: Modeling the Zebrafish Model Organism Toward Reducing, Refining, and Replacing Animal Experiments
CDS
  • 批准号:
    1505832
  • 财政年份:
    2015
  • 资助金额:
    $ 6.98万
  • 项目类别:
    Standard Grant
Never replicate a successful experiment? Standardization, heterogenization and reproducibility in animal experiments
从未复制过成功的实验?
  • 批准号:
    283089959
  • 财政年份:
    2015
  • 资助金额:
    $ 6.98万
  • 项目类别:
    Research Grants
Arrhythmogenic Drug Evaluation System by Simplified Animal Experiments
简化动物实验的致心律失常药物评价系统
  • 批准号:
    26350520
  • 财政年份:
    2014
  • 资助金额:
    $ 6.98万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Promotion of the 4Rs in animal experiments by the development of a production process for polyclonal antibodies using a goldfish
开发金鱼多克隆抗体生产工艺,促进动物实验中的4R
  • 批准号:
    23650227
  • 财政年份:
    2011
  • 资助金额:
    $ 6.98万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
Development of microangiographic systems to visualize cerebular perforating artery in clinical settings and retrobulbar ophthalmic artery arteries in animal experiments.
开发显微血管造影系统,以在临床环境中可视化小脑穿支动脉,并在动物实验中可视化球后眼动脉。
  • 批准号:
    23390305
  • 财政年份:
    2011
  • 资助金额:
    $ 6.98万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
The study for the modification of cerebral synapses by balance exercises in the elderly based on animal experiments.
基于动物实验的老年人平衡运动改变大脑突触的研究。
  • 批准号:
    21500471
  • 财政年份:
    2009
  • 资助金额:
    $ 6.98万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了