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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

批准号：
10671005
负责人：
E Premkumar Reddy
金额：
$ 51.47万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10671005
关键词：
Affinity Affinity Chromatography Apoptotic Binding Biological Models Breast Cancer Cell Breast Cancer Patient Breast Cancer Risk Factor Breast Cancer therapy Breast cancer metastasis CDK4 gene Cancer Cell Growth Cancer Etiology Cell Cycle Cell Death Cell Proliferation Cells Cellular Metabolic Process Cessation of life Chemoresistance Clinical Trials Cyclin-Dependent Kinase Inhibitor 2A Development Diabetes Mellitus Diabetic mouse Diet Disseminated Malignant Neoplasm Drosophila genus ERBB2 gene Exhibits Family Female Gene Family Genes Glycogen Goals Growth High Fat Diet Hyperglycemia Hyperinsulinism Incubated Insulin Resistance Knockout Mice Malignant Neoplasms Mammary Neoplasms Mass Spectrum Analysis Metabolic Pathway Metabolism Methods Modeling Molecular Mouse Mammary Tumor Virus Mus Muscle NUAK1 gene Nature Neoplasm Metastasis Non-Insulin-Dependent Diabetes Mellitus Oncogenes Pathway interactions Patient-derived xenograft models of breast cancer Patients Phenotype Phosphotransferases Physiological Play Prediabetes syndrome Predisposition Process Prognosis Proliferating Property Proteins Recurrent tumor Relapse Resistance Resistance development Risk Role Signal Pathway Technology Testing Therapeutic Therapeutic Agents Translating Tumor Tissue Whole Organism Woman Wood material Work blood glucose regulation cell growth comparison control diabetic effective therapy epidemiology study fasting blood glucose level gain of function glucose metabolism glucose tolerance high risk inhibitor insulin regulation insulin sensitivity insulin signaling kinase inhibitor knock-down malignant breast neoplasm mortality mouse model neoplastic cell non-diabetic overexpression patient derived xenograft model ras Oncogene resistance mechanism small molecule small molecule inhibitor sugar targeted treatment theories therapeutically effective triple-negative invasive breast carcinoma tumor tumor growth tumor progression tumor xenograft

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：
Genes & cancer
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