Exploration of Genome Stability as a Therapeutic Target in Cancer

探索基因组稳定性作为癌症治疗靶点

基本信息

  • 批准号:
    8527030
  • 负责人:
  • 金额:
    $ 3.49万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-04-01 至 2016-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The genome instability seen in many cancers is thought to generate the mutations that drive tumorigenesis (Hanahan and Weinberg 2000). The defects that lead to this instability, however, may be a vulnerability by which cancer cells can be specifically targeted and killed by chemotherapies (D. A. Chan and Giaccia 2011). In the presence of defects causing higher than normal levels of DNA damage, cells may become reliant upon compensating pathways that reduce the impact of the DNA damage and prevent the cells from activating death pathways. If these non-essential compensating mechanisms are now essential in the cancer cells, then treatments inactivating these mechanisms would specifically kill cancer cells in a genotype-specific fashion. This targeting is essentially a therapy-based form of synthetic lethality, which is observed when inactivation of two genes individually has minimal effect, but simultaneous inactivation of both results in decreased cell growth or cell death. The success of poly(ADP-ribose) polymerase (PARP) inhibitors against cancers with defects in the BRCA1 and BRCA2 genes demonstrates that a synthetic lethality inspired approach can be successful in the context of defects in double-strand break (DSB) repair (Bryant et al. 2005; Farmer et al. 2005). Inactivation of PARP is unlikely to be the only mechanism by which BRCA1 and BRCA2 deficient cancers can be targeted. Systematic screening for additional genes or pathways that are required for BRCA1 and BRCA2 deficient cancer cell survival, however, is both expensive and technically challenging due to the requirements for a high-throughput experiment, difficulties in identifying truly lethal conditions, and incomplete inactivation of genes that are knocked down. Here, I will use genetic interactions with mutations in the DSB repair pathway in the yeast Saccharomyces cerevisiae to identify candidate human genes required for the survival of BRCA1 and BRCA2 deficient cancer cell lines. Given the highly conserved nature of the eukaryotic DNA repair mechanisms (Aggarwal and Brosh 2012), I will use previously identified synthetic lethality interactions as well as newly identified interactions giving rise to increased genome instability and increased sensitivity to DNA damaging agents to identify yeast genes of interest. I will then use siRNA knockdown of human homologs of these yeast genes to determine whether equivalent interactions exist in human cancer cell lines. Finally, I will explore if those interactions validated in human cancer cell lines can be used as a target to induce cell death. I expect these experiments will provide a rational approach to identify a highly enriched set of new targets for future therapeutic development.
描述(由申请人提供):在许多癌症中看到的基因组不稳定性被认为会产生驱动肿瘤发生的突变(Hanahan and Weinberg 2000)。然而,导致这种不稳定的缺陷可能是癌细胞可以通过的脆弱性 特别针对化学疗法的目标和杀死(D. A. Chan和Giaccia 2011)。在存在导致DNA损伤水平高于正常水平的缺陷的情况下,细胞可能在补偿途径的情况下依赖于减少DNA损伤的影响并防止细胞激活死亡途径。如果这些非必需的补偿机制现在在癌细胞中至关重要,那么灭活这些机制的处理将以基因型特异性的方式特异性杀死癌细胞。该靶向基本上是一种基于治疗的合成致死性的形式,当两个基因的失活分别灭活时,可以观察到,但同时失活两种基因会导致细胞生长或细胞死亡的降低。聚(ADP-核糖)聚合酶(PARP)抑制剂针对BRCA1和BRCA2基因缺陷的癌症的成功表明,在双层破裂(DSB)修复中缺陷(Bryant etal。2005; Farmer et er.2005; 2005年)中,合成致死性启发的方法可以成功。 PARP的灭活不可能是BRCA1和BRCA2缺乏癌症的唯一机制。然而,由于对高通量实验的要求,在识别真正致命的状况方面的困难,对BRCA1和BRCA2缺乏癌细胞存活所需的其他基因或途径的系统筛查既昂贵又具有挑战性。 并且不完全失活的基因被击倒。在这里,我将在酿酒酵母中使用DSB修复途径中的突变进行遗传相互作用,以鉴定BRCA1和BRCA2缺乏癌细胞系所需的候选人基因。鉴于真核DNA修复机制的高度保守性(Aggarwal和Brosh 2012),我将使用先前鉴定的合成致死性相互作用以及新的 确定的相互作用导致基因组不稳定性增加,并提高对DNA损害剂的敏感性,以鉴定酵母菌基因。然后,我将使用这些酵母基因的人类同源物的siRNA敲低来确定人类癌细胞系中是否存在等效相互作用。最后,我将探讨是否可以将那些在人类癌细胞系中验证的相互作用用作诱导细胞死亡的靶标。我希望这些实验将提供一种合理的方法,以确定一组非常丰富的新目标,以实现未来的治疗发展。

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 }}

Rahul Nene其他文献

Rahul Nene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('Rahul Nene', 18)}}的其他基金

Exploration of Genome Stability as a Therapeutic Target in Cancer
探索基因组稳定性作为癌症治疗靶点
  • 批准号:
    8639355
  • 财政年份:
    2013
  • 资助金额:
    $ 3.49万
  • 项目类别:

相似国自然基金

BRCA1/2基因不同突变位点对对侧乳腺癌发病风险的差异影响及其机制探索
  • 批准号:
    82372717
  • 批准年份:
    2023
  • 资助金额:
    49 万元
  • 项目类别:
    面上项目
调控BRCA1突变乳腺癌PARP抑制剂应答的关键增强子及其下游基因研究
  • 批准号:
  • 批准年份:
    2023
  • 资助金额:
    220 万元
  • 项目类别:
调控BRCA1突变乳腺癌PARP抑制剂应答的关键增强子及其下游基因研究
  • 批准号:
    82330090
  • 批准年份:
    2023
  • 资助金额:
    220.00 万元
  • 项目类别:
    重点项目
BRCA1单倍剂量不足效应诱导产生的机制及其与基因组不稳定和杂合突变致癌的联系
  • 批准号:
  • 批准年份:
    2021
  • 资助金额:
    54.7 万元
  • 项目类别:
    面上项目
BRCA1单倍剂量不足效应诱导产生的机制及其与基因组不稳定和杂合突变致癌的联系
  • 批准号:
    82172951
  • 批准年份:
    2021
  • 资助金额:
    55.00 万元
  • 项目类别:
    面上项目

相似海外基金

Mechanisms of Parp inhibitor-induced bone marrow toxicities
Parp 抑制剂诱导骨髓毒性的机制
  • 批准号:
    10637962
  • 财政年份:
    2023
  • 资助金额:
    $ 3.49万
  • 项目类别:
Synergize a novel homologous recombination inhibitor with DNA damagingagents in TNBC
在 TNBC 中协同新型同源重组抑制剂与 DNA 损伤剂
  • 批准号:
    10760604
  • 财政年份:
    2023
  • 资助金额:
    $ 3.49万
  • 项目类别:
Highly specific ATR inhibitors for the targeted treatment of a broad spectrum of cancers
高度特异性的 ATR 抑制剂,用于多种癌症的靶向治疗
  • 批准号:
    9202326
  • 财政年份:
    2016
  • 资助金额:
    $ 3.49万
  • 项目类别:
FASEB SRC on Genetic Recombination and Genome Rearrangements
FASEB SRC 关于基因重组和基因组重排
  • 批准号:
    8978686
  • 财政年份:
    2015
  • 资助金额:
    $ 3.49万
  • 项目类别:
Uncovering Breast Cancer Predisposition Factors in Puerto Rico
揭示波多黎各的乳腺癌易感因素
  • 批准号:
    8728153
  • 财政年份:
    2014
  • 资助金额:
    $ 3.49万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了