Exploiting synthetic-lethal interactions to target triple-negative breast cancers

利用合成致死相互作用来靶向三阴性乳腺癌

基本信息

  • 批准号:
    9269527
  • 负责人:
  • 金额:
    $ 23.94万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-04-01 至 2018-03-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT No targeted therapeutic strategies are currently available against triple-negative (TN) breast cancer, the most difficult-to-treat form of breast cancer, which does not overexpress human epidermal growth factor receptor 2 (HER2) and lacks the expression of the estrogen and progesterone receptors. Thus, there is an urgent need in deepening our understanding of this aggressive breast cancer subtype and identifying clinically relevant targets for therapeutic intervention. We have recently discovered that an oncogenic transcription factor MYC as well as the MYC-dependent signaling pathways are significantly up-regulated in primary human triple-negative breast tumors. In addition, we found that MYC activation is associated with patientsʼ poor prognosis suggesting that the MYC pathways may play a fundamental role in driving the formation of these aggressive tumors. How can we kill MYC-driven TN tumors? Because MYC is a transcription factor, rationally designed small molecule inhibitors that can directly inhibit its activity are not available for clinical use. An alternative approach in selectively killing MYC-driven tumors is to exploit the existence of “synthetic-lethal” interactions. Our group previously took a cell cycle-biased approach and discovered that inhibition of the mitotic kinase cyclin-dependent kinase (CDK) 1 resulted in apoptosis in cells engineered to overexpress MYC. The mechanism of such cell death involved an up-regulation of a pro-apoptotic BCL-2 family member BIM. We subsequently used this approach to treat TN cell lines and xenograft tumors with elevated MYC expression. These observations suggest that MYC-dependent synthetic-lethal interactions exist, and importantly, can be targeted to selectively kill MYC-driven tumors. Aim 1 of this proposed research will further study the clinical potential of small molecule CDK inhibition against MYC-driven TN cancers particularly in combination with clinical inhibitors of anti-apoptotic BCL-2 members. This is based on our novel hypothesis that, because CDK inhibition up-regulates BIM and activates mitochondrial intrinsic pathway, the combined use of the inhibitors for CDK and anti-apoptotic BCL-2 family members may significantly enhance the rate of cell death. Aim 2 will characterize a newly discovered synthetic-lethal interaction between MYC activation and inhibition of Pim1, a non-essential, kinase previously shown to genetically interact with MYC. Aim 3 will conduct a high-throughout small molecule screen to identify potential lead molecules capable of inducing MYC-dependent synthetic lethality in mammary cells. We will carry out these experiments using a combination of model human mammary epithelial cells, genetically defined cancer cell lines, and a panel of novel human-in-mouse orthotopic tumor grafts models. If successful, the proposed research will not only expand our knowledge on MYC biology but will also provide novel therapeutic concepts to be tested again patients with TN tumors.
项目总结/文摘

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Antineoplastic effects of selective CDK9 inhibition with atuveciclib on cancer stem-like cells in triple-negative breast cancer.
  • DOI:
    10.18632/oncotarget.26468
  • 发表时间:
    2018-12-18
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Brisard, Daphne;Eckerdt, Frank;Platanias, Leonidas C
  • 通讯作者:
    Platanias, Leonidas C
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Dai Horiuchi其他文献

Dai Horiuchi的其他文献

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{{ truncateString('Dai Horiuchi', 18)}}的其他基金

Investigating Rational Combination Therapies for Triple-Negative Breast Cancer
研究三阴性乳腺癌的合理联合疗法
  • 批准号:
    10367060
  • 财政年份:
    2022
  • 资助金额:
    $ 23.94万
  • 项目类别:
Investigating Rational Combination Therapies for Triple-Negative Breast Cancer
研究三阴性乳腺癌的合理联合疗法
  • 批准号:
    10543989
  • 财政年份:
    2022
  • 资助金额:
    $ 23.94万
  • 项目类别:
Exploiting synthetic-lethal interactions to target triple-negative breast cancers
利用合成致死相互作用来靶向三阴性乳腺癌
  • 批准号:
    9070742
  • 财政年份:
    2015
  • 资助金额:
    $ 23.94万
  • 项目类别:
Exploiting synthetic-lethal interactions to target triple-negative breast cancers
利用合成致死相互作用来靶向三阴性乳腺癌
  • 批准号:
    8487128
  • 财政年份:
    2013
  • 资助金额:
    $ 23.94万
  • 项目类别:
Exploiting synthetic-lethal interactions to target triple-negative breast cancers
利用合成致死相互作用来靶向三阴性乳腺癌
  • 批准号:
    8639510
  • 财政年份:
    2013
  • 资助金额:
    $ 23.94万
  • 项目类别:

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