Targeting the ATR pathway in p53-deficient cancers

靶向 p53 缺陷癌症中的 ATR 通路

基本信息

  • 批准号:
    8300806
  • 负责人:
  • 金额:
    $ 34.03万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-07-13 至 2016-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Cancer cells that harbor inactivating p53 mutations exhibit checkpoint defects and impaired DNA damage responses. Because p53 mutations are prevalent in many common cancers, strategies that would exploit these defects are predicted to have significant clinical impact. This proposal is focused on the ATR pathway, which has recently emerged as a critical modulator of p53-deficient cancer cell survival in response to therapeutic agents. The ATR kinase holoenzyme is activated by DNA damage and DNA replication stress, and is therefore responsive to many of the anticancer agents currently in use. Recent studies have revealed new mechanisms by which ATR is controlled. These insights provide new opportunities to target this pathway. This proposed project employs genetic and biochemical methods to study the protein-protein interactions that define the competent ATR complex, and the effects of common chemotherapeutic agents on complex formation. The effectiveness of targeting distinct upstream and downstream components of the ATR pathway, including Cdk2 and Chk1, will be comparatively evaluated in vitro and in vivo. In a coordinated effort, a pharmacogenetic array of approved drugs will be screened to identify new ATR activators. Human somatic cells with targeted genetic alterations will be used to identify new drug/target combinations. A focused effort will be made to screen for genes that promote survival in response to cisplatin, an anticancer drug recently found to induce distinct survival pathways in cells that are deficient for p53. The long-term objectives of this project are to reveal basic mechanisms of ATR regulation, new drug targets, and new strategies for generating synthetic lethality in p53-deficient human cancer cells.
描述(由申请人提供):携带失活p53突变的癌细胞表现出检查点缺陷和受损的DNA损伤反应。由于p53突变在许多常见癌症中普遍存在,因此预测利用这些缺陷的策略将具有显著的临床影响。这项建议的重点是ATR途径,这是最近出现的p53缺陷的癌细胞生存的治疗药物的关键调制器。ATR激酶全酶被DNA损伤和DNA复制应激激活,因此对目前使用的许多抗癌剂有反应。最近的研究揭示了ATR控制的新机制。这些见解为瞄准这一途径提供了新的机会。该项目采用遗传学和生物化学方法来研究定义ATR复合物的蛋白质-蛋白质相互作用,以及常见化疗药物对复合物形成的影响。靶向ATR途径的不同上游和下游组分(包括Cdk 2和Chk 1)的有效性将在体外和体内进行比较评估。在一项协调努力中,将筛选批准药物的药物遗传学阵列,以确定新的ATR激活剂。具有靶向遗传改变的人类体细胞将用于鉴定新的药物/靶标组合。一个集中的努力将作出筛选基因,促进生存的反应顺铂,抗癌药物最近发现,诱导不同的生存途径的细胞缺乏p53。该项目的长期目标是揭示ATR调节的基本机制,新的药物靶点,以及在p53缺陷的人类癌细胞中产生合成致死性的新策略。

项目成果

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{{ truncateString('FRED BUNZ', 18)}}的其他基金

Synthetic adenovirus libraries for vector optimization
用于载体优化的合成腺病毒文库
  • 批准号:
    10460635
  • 财政年份:
    2019
  • 资助金额:
    $ 34.03万
  • 项目类别:
Synthetic adenovirus libraries for vector optimization
用于载体优化的合成腺病毒文库
  • 批准号:
    10188568
  • 财政年份:
    2019
  • 资助金额:
    $ 34.03万
  • 项目类别:
Synthetic adenovirus libraries for vector optimization
用于载体优化的合成腺病毒文库
  • 批准号:
    10021682
  • 财政年份:
    2019
  • 资助金额:
    $ 34.03万
  • 项目类别:
A Genetic Model for Early-Onset Breast and Colon Cancer in African Americans
非裔美国人早发乳腺癌和结肠癌的遗传模型
  • 批准号:
    8662394
  • 财政年份:
    2013
  • 资助金额:
    $ 34.03万
  • 项目类别:
Summer Translational Oncology Program (STOP)
夏季转化肿瘤学项目(STOP)
  • 批准号:
    8865576
  • 财政年份:
    2013
  • 资助金额:
    $ 34.03万
  • 项目类别:
A Genetic Model for Early-Onset Breast and Colon Cancer in African Americans
非裔美国人早发乳腺癌和结肠癌的遗传模型
  • 批准号:
    9096071
  • 财政年份:
    2013
  • 资助金额:
    $ 34.03万
  • 项目类别:
Summer Translational Oncology Program (STOP)
夏季转化肿瘤学项目(STOP)
  • 批准号:
    8413758
  • 财政年份:
    2013
  • 资助金额:
    $ 34.03万
  • 项目类别:
A Genetic Model for Early-Onset Breast and Colon Cancer in African Americans
非裔美国人早发乳腺癌和结肠癌的遗传模型
  • 批准号:
    8704891
  • 财政年份:
    2013
  • 资助金额:
    $ 34.03万
  • 项目类别:
A Genetic Model for Early-Onset Breast and Colon Cancer in African Americans
非裔美国人早发乳腺癌和结肠癌的遗传模型
  • 批准号:
    8389392
  • 财政年份:
    2012
  • 资助金额:
    $ 34.03万
  • 项目类别:
Targeting the ATR pathway in p53-deficient cancers
靶向 p53 缺陷癌症中的 ATR 通路
  • 批准号:
    8082529
  • 财政年份:
    2011
  • 资助金额:
    $ 34.03万
  • 项目类别:

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