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: 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
• 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

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.

项目摘要/摘要 管理肿瘤复发和扩散是乳腺癌的主要挑战。这种情况进一​​步汇总 对于许多流行病学研究，糖尿病的女性表明，2型糖尿病的女性处于 与女性相比 不是糖尿病。研究表明，与2型糖尿病相关的高胰岛素血症是重要的 乳腺癌患者死亡率的因素，表明对有效疗法的重要需求 在高胰岛素条件下抑制肿瘤细胞增殖。我们的早期研究表明CDK4敲击 熄灭小鼠无法通过ERBB2或Ras Oncogenes驱动乳腺癌，这表明CDK4/6 抑制剂可能是某些乳腺癌的有效治疗剂。批准CDK4/6抑制剂为 乳腺癌疗法证实了这一理论。另一个在胰岛素信号传导中起关键作用的激酶 癌症的进展为NUAK1/ARK5，属于调节代谢的AMPK基因家族。 Nuak1/ark5在整个生物体中扮演的正常生理作用是使用 肌肉特异性敲除小鼠，表明Nuak1通过 调节胰岛素信号传导。那就是，当这些淘汰小鼠被喂养高脂饮食时 暴露了较低的空腹血糖水平，更大的葡萄糖耐受性，较高的胰岛素敏感性和 与对照小鼠相比，较高浓度的肌肉糖原表明抑制 ARK5/NUAK1可以克服高血糖的影响。有趣的是，ARK5最初是确定的 由于转移基因及其过表达已被证明可以促进几种肿瘤的转移 类型。为了实现抑制乳腺肿瘤细胞生长和代谢的目标，我们开发了潜在的双重 CDK4和ARK5的抑制剂（ON123300），这是非常有效的乳腺肿瘤生长抑制剂。在 此外，该化合物对高糖饮食诱导的肿瘤发展产生了深远的影响， 果蝇模型系统中的转移。在此应用中，我们建议将这些研究扩展到鼠标模型 由Leroith博士和三重阴性乳腺癌的PDX模型开发的高胰岛素血症（MKR小鼠） （TNBC）由Irie博士开发。目的是：（1）测试ON123300对生长和转移的影响 MKR小鼠中乳腺肿瘤暴露了高胰岛素，糖尿病前表型； （2）检查 高胰岛血症对PDX乳腺肿瘤生长和转移的影响，并利用模型 ARK5的最高相对水平检查了ON123300的治疗值； （3）使用新的 开发的多路复用激酶抑制剂珠（MIB）和“癌症工具包功能收益”（CTK）技术 确定乳腺癌细胞在长时间暴露和对ON123300的抗性和对 确定可能是这种电阻根本原因的信号通路的性质。

项目成果

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
• 作者: Baker, Stacey J;Poulikakos, Poulikos I;Irie, Hanna Y;Parekh, Samir;Reddy, E Premkumar
• 通讯作者: Reddy, E Premkumar