Targeting cell cycle and metabolic pathways of high risk breast cancers using mouse models of hyperinsulinemia

使用高胰岛素血症小鼠模型靶向高风险乳腺癌的细胞周期和代谢途径

基本信息

项目摘要

Project Summary/Abstract Managing tumor recurrence and spread is a major challenge in breast cancer. This scenario is further aggravated for women with diabetes as numerous epidemiological studies show that women with type 2 diabetes are at significantly greater risk of developing, relapsing with, and dying from breast cancer compared to women who are not diabetic. Studies show that hyperinsulinemia associated with type 2 diabetes is a significant contributing factor for the mortality seen in breast cancer patients, suggesting an important need for effective therapies that inhibit tumor cell proliferation under hyperinsulinemic conditions. Our early studies showed that cdk4 knock- out mice fail to develop breast cancers driven by the ERBB2 or RAS oncogenes suggesting that CDK4/6 inhibitors may be effective therapeutic agents for certain breast cancers. The approval of CDK4/6 inhibitors as breast cancer therapeutics validated this theory. Another kinase which plays a critical role in insulin signaling and cancer progression is NUAK1/ARK5 which belongs to the AMPK gene family which regulate metabolism. The normal physiological role played by NUAK1/ARK5 in the whole organism was studied using muscle-specific knock-out mice which showed that NUAK1 controls glucose metabolism through regulation of the insulin signaling. Thus, when these knock-out mice were fed a high fat diet, they exhibited a lower fasting blood glucose level, greater glucose tolerance, higher insulin sensitivity, and higher concentrations of muscle glycogen compared to control mice suggesting that inhibition of ARK5/NUAK1 can overcome the effects of hyperglycemia. Interestingly, ARK5 was originally identified as a metastasis gene and its over-expression has been shown to promote metastasis of several tumor types. To achieve the goal of inhibiting breast tumor cell growth and metabolism, we developed a potent dual inhibitor of CDK4 and ARK5 (ON123300), which was a very effective inhibitor of breast tumor growth. In addition, this compound has shown a profound effect on high sugar diet-induced tumor development and metastasis in a Drosophila model system. In this application, we propose to extend these studies to mouse models of hyperinsulinemia (MKR mice), developed by Dr. LeRoith and PDX models of Triple Negative Breast cancer (TNBCs) developed by Dr. Irie. The aims are: (1) To test the effects of ON123300 on the growth and metastasis of mammary tumors in MKR mice which exhibit hyperinsulinemic, pre-diabetic phenotype; (2) To examine the effects of hyperinsuminemia on the growth and metastasis of PDX breast tumors and utilize the models with the highest relative levels of ARK5 to examine the therapeutic value of ON123300; and (3) To use the newly developed Multiplexed-kinase Inhibitor Beads (MIB) and “Cancer Toolkit gain-of-function” (CTK) technologies to determine whether breast cancer cells develop resistance to ON123300 upon prolonged exposure and to determine the nature of signaling pathways that might be the root cause of such resistance.
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)
CDK4: a master regulator of the cell cycle and its role in cancer.
  • DOI:
    10.18632/genesandcancer.221
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Baker, Stacey J;Poulikakos, Poulikos I;Irie, Hanna Y;Parekh, Samir;Reddy, E Premkumar
  • 通讯作者:
    Reddy, E Premkumar
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E Premkumar Reddy其他文献

IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled
白细胞介素 3 信号传导以及 Src 激酶、JAK 和 STAT 的作用:一个隐蔽的联络被揭示
  • DOI:
    10.1038/sj.onc.1203594
  • 发表时间:
    2000-05-25
  • 期刊:
  • 影响因子:
    7.300
  • 作者:
    E Premkumar Reddy;Anita Korapati;Priya Chaturvedi;Sushil Rane
  • 通讯作者:
    Sushil Rane
Janus kinases: components of multiple signaling pathways
Janus 激酶:多条信号通路的组成部分
  • DOI:
    10.1038/sj.onc.1203925
  • 发表时间:
    2000-11-20
  • 期刊:
  • 影响因子:
    7.300
  • 作者:
    Sushil G Rane;E Premkumar Reddy
  • 通讯作者:
    E Premkumar Reddy
The myb gene family in cell growth, differentiation and apoptosis
细胞生长、分化和凋亡中的 myb 基因家族
  • DOI:
    10.1038/sj.onc.1202839
  • 发表时间:
    1999-05-13
  • 期刊:
  • 影响因子:
    7.300
  • 作者:
    Il-Hoan Oh;E Premkumar Reddy
  • 通讯作者:
    E Premkumar Reddy
JAKs, STATs and Src kinases in hematopoiesis
造血过程中的 JAKs、STATs 和 Src 激酶
  • DOI:
    10.1038/sj.onc.1205398
  • 发表时间:
    2002-05-21
  • 期刊:
  • 影响因子:
    7.300
  • 作者:
    Sushil G Rane;E Premkumar Reddy
  • 通讯作者:
    E Premkumar Reddy
Signaling by dual specificity kinases
双特异性激酶的信号传导
  • DOI:
    10.1038/sj.onc.1202251
  • 发表时间:
    1998-09-22
  • 期刊:
  • 影响因子:
    7.300
  • 作者:
    N Dhanasekaran;E Premkumar Reddy
  • 通讯作者:
    E Premkumar Reddy

E Premkumar Reddy的其他文献

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{{ truncateString('E Premkumar Reddy', 18)}}的其他基金

Targeting FL3 and SRC kinases for AML therapy
靶向 FL3 和 SRC 激酶进行 AML 治疗
  • 批准号:
    10658259
  • 财政年份:
    2023
  • 资助金额:
    $ 51.47万
  • 项目类别:
Targeting cell cycle and metabolic pathways of high risk breast cancers using mouse models of hyperinsulinemia
使用高胰岛素血症小鼠模型靶向高风险乳腺癌的细胞周期和代谢途径
  • 批准号:
    10199970
  • 财政年份:
    2020
  • 资助金额:
    $ 51.47万
  • 项目类别:
Targeting cell cycle and metabolic pathways of high risk breast cancers using mouse models of hyperinsulinemia
使用高胰岛素血症小鼠模型靶向高风险乳腺癌的细胞周期和代谢途径
  • 批准号:
    10029076
  • 财政年份:
    2020
  • 资助金额:
    $ 51.47万
  • 项目类别:
Targeting cell cycle and metabolic pathways of high risk breast cancers using mouse models of hyperinsulinemia
使用高胰岛素血症小鼠模型靶向高风险乳腺癌的细胞周期和代谢途径
  • 批准号:
    10457279
  • 财政年份:
    2020
  • 资助金额:
    $ 51.47万
  • 项目类别:
Targeting CDK4 in TGS-B Inactivated Gastrointestinal Cancers
TGS-B 灭活胃肠道癌中靶向 CDK4
  • 批准号:
    8744873
  • 财政年份:
    2013
  • 资助金额:
    $ 51.47万
  • 项目类别:
Targeting Mitotic Kinases Inhibitors for Cancer Therapy
靶向有丝分裂激酶抑制剂用于癌症治疗
  • 批准号:
    8985660
  • 财政年份:
    2012
  • 资助金额:
    $ 51.47万
  • 项目类别:
Targeting Mitotic Kinases Inhibitors for Cancer Therapy
靶向有丝分裂激酶抑制剂用于癌症治疗
  • 批准号:
    8787991
  • 财政年份:
    2012
  • 资助金额:
    $ 51.47万
  • 项目类别:
Targeting Mitotic Kinases Inhibitors for Cancer Therapy
靶向有丝分裂激酶抑制剂用于癌症治疗
  • 批准号:
    8435360
  • 财政年份:
    2012
  • 资助金额:
    $ 51.47万
  • 项目类别:
Targeting Mitotic Kinases Inhibitors for Cancer Therapy
靶向有丝分裂激酶抑制剂用于癌症治疗
  • 批准号:
    8238575
  • 财政年份:
    2012
  • 资助金额:
    $ 51.47万
  • 项目类别:
Role of C-myb in Hematopoiesis and Cancer
C-myb 在造血和癌症中的作用
  • 批准号:
    7629613
  • 财政年份:
    2007
  • 资助金额:
    $ 51.47万
  • 项目类别:

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用于药物发现的细胞膜亲和层析试剂盒
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