Novel regulation of PI3K/Akt to direct targeted breast cancer therapies

PI3K/Akt 的新调控可指导乳腺癌靶向治疗

基本信息

  • 批准号:
    8702122
  • 负责人:
  • 金额:
    $ 35.02万
  • 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:
    2013-07-16 至 2018-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The PI 3-K/Akt signaling axis is critical for both the initiation and progression of many cancers, including breast cancer, by promoting cancer cell survival and growth. Akt hyperactivation is observed in a large proportion of patients and is considered a hallmark of cancer. Much is known concerning the mechanisms that govern PI 3- K activation, and in turn Akt regulation and signaling to phenotypes associated with malignancy. This molecular information has enabled the development of PI 3-K and Akt inhibitors for cancer therapy, and many of these are in phase I and II trials. However, small molecule Akt inhibitors have shown side effects with toxicity in normal somatic cells, reflecting the fact that Akt is essential for various normal cellular functions. In contrast, uncontrolled cell division is another hallmark of human cancer, whereas most normal somatic cells are in a non-dividing, quiescent state. Consequently, certain cell cycle regulators such as Cyclin A, frequently overexpressed in cancer, are considered promising anti-cancer targets. To date, an intrinsic connection between Akt hyperactivation and aberrant cell cycle regulation has not been defined. Our preliminary studies show that Akt activity fluctuates during cell cycle and mirrors Cyclin A expression. Moreover, depletion of Cyclin A or Cdk2 dramatically reduces Akt activity, suggesting that Cdk2/Cyclin A inhibitors may specifically kill breast cancer cells with no effect of normal somatic cells. In Aim 1, we propose that aberrant activation of Cdk2/Cyclin A in breast cancer contributes to hyperactivation of Akt. We will mechanistically define how Cdk2/Cyclin A functions as a novel upstream regulatory mechanism to promote Akt activation in a cell cycle- dependent manner. We will determine whether Cdk2 inhibitors can suppress breast cancer cell growth in vitro and in vivo. In Aim 2, we show preliminary evidence that in a subset of triple-negative breast cancer cells, reactivation of Akt occurs subsequent to PI 3-K inhibition, and in a manner dependent on the E3 ubiquitin ligase Skp2. We will investigate the mechanistic basis for Skp2-mediated reactivation of Akt to drive phenotypes associated with malignancy in breast cancer cells. Furthermore, somatic mutations in Akt1 and Akt2 at E17K have been identified in breast cancer patients. In our preliminary studies, we show that Akt2 E17K can promote signaling and proliferation of breast epithelial cells in a growth factor and PI 3-K- independent manner, whereas Akt1 E17K cannot. We will explore the mechanistic basis for this distinction in vitro and using transgenic mice expressing Akt1 and Akt2 E17K, and examine the contribution of Skp2 in this event. Our goal in Aim 2 is to define the precise mechanisms that govern Akt activation in a PI 3-K- independent manner in breast cancer. Overall, we believe that our proposed studies will provide new molecular insights into the activation of Akt in breast tumors, that would be unresponsive to PI 3-K inhibitors. Instead, our studies will inform the use of Cdk2, Skp2 and Akt inhibitors for targeted therapy to achieve optimal treatment efficacy in the clinic.
描述(由申请人提供):pi3 - k /Akt信号轴通过促进癌细胞的存活和生长,对包括乳腺癌在内的许多癌症的发生和进展至关重要。在很大比例的患者中观察到Akt过度激活,这被认为是癌症的标志。关于调控PI 3- K活化的机制,以及Akt调控和信号传导与恶性肿瘤相关的表型,我们已经知道很多。这些分子信息促进了用于癌症治疗的PI 3-K和Akt抑制剂的开发,其中许多都处于I期和II期试验中。然而,小分子Akt抑制剂在正常体细胞中显示出副作用和毒性,这反映了Akt对各种正常细胞功能至关重要的事实。相反,不受控制的细胞分裂是另一种情况

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)

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Alex Toker其他文献

Alex Toker的其他文献

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{{ truncateString('Alex Toker', 18)}}的其他基金

FASEB Science Research Conference: Protein Kinases and Protein Phosphorylation
FASEB 科学研究会议:蛋白激酶和蛋白磷酸化
  • 批准号:
    10464756
  • 财政年份:
    2022
  • 资助金额:
    $ 35.02万
  • 项目类别:
Discovery, Regulation and Function of the PI 3-Kinase and AKT Pathway in Cancer
PI 3 激酶和 AKT 通路在癌症中的发现、调节和功能
  • 批准号:
    10246864
  • 财政年份:
    2020
  • 资助金额:
    $ 35.02万
  • 项目类别:
Discovery, Regulation and Function of the PI 3-Kinase and AKT Pathway in Cancer
PI 3 激酶和 AKT 通路在癌症中的发现、调节和功能
  • 批准号:
    10677761
  • 财政年份:
    2020
  • 资助金额:
    $ 35.02万
  • 项目类别:
Discovery, Regulation and Function of the PI 3-Kinase and AKT Pathway in Cancer
PI 3 激酶和 AKT 通路在癌症中的发现、调节和功能
  • 批准号:
    10471296
  • 财政年份:
    2020
  • 资助金额:
    $ 35.02万
  • 项目类别:
Exploiting Metabolic Vulnerabilities in the PI3K and Akt Pathway in Cancer for Therapeutic Benefit
利用癌症 PI3K 和 Akt 通路中的代谢漏洞获得治疗效果
  • 批准号:
    9903255
  • 财政年份:
    2016
  • 资助金额:
    $ 35.02万
  • 项目类别:
Exploiting Metabolic Vulnerabilities in the PI3K and Akt Pathway in Cancer for Therapeutic Benefit
利用癌症 PI3K 和 Akt 通路中的代谢漏洞获得治疗效果
  • 批准号:
    9270532
  • 财政年份:
    2016
  • 资助金额:
    $ 35.02万
  • 项目类别:
Identifying lincRNAs that Mediate PI 3 Kinase Dependent Breast Cancer
鉴定介导 PI 3 激酶依赖性乳腺癌的 lincRNA
  • 批准号:
    8610428
  • 财政年份:
    2014
  • 资助金额:
    $ 35.02万
  • 项目类别:
Novel regulation of PI3K/Akt to direct targeted breast cancer therapies
PI3K/Akt 的新调控可指导乳腺癌靶向治疗
  • 批准号:
    9812868
  • 财政年份:
    2013
  • 资助金额:
    $ 35.02万
  • 项目类别:
Novel regulation of PI3K/Akt to direct targeted breast cancer therapies
PI3K/Akt 的新调控可指导乳腺癌靶向治疗
  • 批准号:
    8870311
  • 财政年份:
    2013
  • 资助金额:
    $ 35.02万
  • 项目类别:
Novel regulation of PI3K/Akt to direct targeted breast cancer therapies
PI3K/Akt 的新调控可指导乳腺癌靶向治疗
  • 批准号:
    8559337
  • 财政年份:
    2013
  • 资助金额:
    $ 35.02万
  • 项目类别:

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