Targeting 6-Phosphofructo-2-Kinase to increase efficacy of CDK4/6 Inhibitors

靶向 6-Phosphofructo-2-Kinase 以提高 CDK4/6 抑制剂的功效

基本信息

批准号：
10650304
负责人：
YOANNIS IMBERT-FERNANDEZ
金额：
$ 34.97万
依托单位：
UNIVERSITY OF LOUISVILLE
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：
2020-07-09 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650304
关键词：
6-Phosphofructo-2-kinase 6-Phosphofructokinase Attenuated Automobile Driving Binding Biological Availability Breast Adenocarcinoma Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer cell line Bypass CDK4 gene Cell Cycle Cell Cycle Progression Cells Clinical Clinical Trials Cyclin D1 Cyclins Development ERBB2 gene Enzymes Estradiol Estrogen Receptors Estrogen receptor positive FDA approved Fructose Genetic Genetic Transcription Glucose Glycolysis Glycolysis Induction Growth In Vitro Malignant Neoplasms Mediating Metabolic Metastatic breast cancer Oncogenic Oral Pathway interactions Patients Phase Phase I/II Trial Phosphorylation Progression-Free Survivals Proliferating Relapse Resistance Resistance development Retinoblastoma Protein Role Testing Time advanced breast cancer base blood glucose regulation cancer cell combinatorial cyclin D3 cyclin-dependent kinase 6 design early phase clinical trial efficacious treatment glucose metabolism hormone receptor-positive hormone therapy improved in vivo inhibitor malignant breast neoplasm mouse model novel novel strategies overexpression pharmacologic prevent rational design research clinical testing response targeted treatment therapy resistant treatment response tumor

项目摘要

We have recently discovered a novel oncogenic mechanism whereby cyclin D1 bypasses CDK4/6 inhibition resulting in the stimulation of 6-phosphofructo-2-kinase (PFKFB3) and glucose metabolism. The objective of this proposal is to characterize the role of PFKFB3 in mediating adaptation or resistance to CDK4/6 inhibition and to define new approaches to increase the efficacy of CDK4/6 inhibitors in order to enable durable responses in stage IV HR+ breast cancer patients. Deregulation of the estrogen receptor (ER)-cyclin D1-CDK4/6 pathway is a hallmark of ER+ breast cancer that has prompted the development of CDK4/6 inhibitors. Although administration of CDK4/6 inhibitors to patients with ER+ advanced breast cancers have resulted in an improvement in progression free survival, almost all patients invariable develop resistance and relapse over time. Activation of glucose metabolism upon CDK4/6 inhibition is becoming increasingly evident. A key stimulator of glycolysis is the PFKFB3 enzyme which synthesizes fructose 2,6-bisphosphate (F2,6BP), a potent allosteric activator of the rate-limiting 6-phosphofructo-1-kinase (PFK1). F2,6BP controls flux throughout the entire glycolytic pathway and, as a result is required for the proliferation of cancer cells. In preliminary studies, we provide evidence that PFKFB3 expression and activity is increased in response to CDK4 inhibition in ER+ breast cancer cells and breast cancer patient tumors. Notably, we show that a PFKFB3 inhibitor, PFK-158, increases the anti-tumor activity of anti-CDK4 targeted therapy in vitro and in vivo. We postulate that PFKFB3 is an essential regulatory effector of the cyclin D1-CDK4/6 axis that serves to attenuate CDK4/6 inhibition effects by stimulating glucose metabolism. Furthermore, we hypothesize that genetic or pharmacological inhibition of PFKFB3 will increase the efficacy of CDK4/6 inhibitors by disabling the ability of the cell to sustain sufficient glucose metabolism necessary for survival and growth. Aim 1 will determine the mechanism by which CDK4/6 inhibition induces PFKFB3 expression. Aim 2 will determine the effects of combined CDK4/6 and PFKFB3 inhibition on glucose metabolism, cell cycle, growth and survival in vitro. Aim 3 will examine the metabolic and growth effects of pharmacological CDK4/6 and PFKFB3 inhibition as monotherapies and in combination in mouse models of breast cancer in vivo. We anticipate that our studies will support the clinical testing of PFKFB3 inhibitors in combination with CDK4/6 inhibitors to increase the survival of advanced ER+ breast cancer patients.

我们最近发现了一种新型的致癌机制，Cyclin D1绕过CDK4/6抑制导致刺激6-磷酸2-激酶（PFKFB3）和葡萄糖代谢。这个目的建议是表征PFKFB3在介导适应或对CDK4/6抑制的抗性和对的作用定义新方法以提高CDK4/6抑制剂的功效，以便在 IV期HR+乳腺癌患者。雌激素受体（ER）-CRYCLIN D1-CDK4/6途径的放松管制是 ER+乳腺癌的标志是促使CDK4/6抑制剂的发展。虽然给予ER+晚期乳腺癌患者的CDK4/6抑制剂已导致随着时间的流逝，几乎所有患者都会发展耐药性和复发，几乎所有患者都会有所改善。 CDK4/6抑制作用上葡萄糖代谢的激活变得越来越明显。一个关键刺激器糖酵解是PFKFB3酶，它合成了2,6-双磷酸果糖（F2,6bp）的果糖，这是一种有效的变构型限速限制6-磷酸1-激酶的激活剂（PFK1）。 F2,6bp控制整个通量糖尿细胞增殖需要糖酵解途径，因此需要。在初步研究中，我们提供证据表明PFKFB3的表达和活性因ER+乳房的CDK4抑制而增加癌细胞和乳腺癌患者肿瘤。值得注意的是，我们表明PFKFB3抑制剂PFK-158增加抗CDK4靶向治疗的抗肿瘤活性在体外和体内。我们假设PFKFB3是细胞周期蛋白D1-CDK4/6轴的基本调节效应子，该轴可通过刺激葡萄糖代谢。此外，我们假设遗传或药理抑制 PFKFB3将通过禁用细胞维持足够的能力来提高CDK4/6抑制剂的功效生存和生长所需的葡萄糖代谢。 AIM 1将确定CDK4/6的机制抑制诱导PFKFB3表达。 AIM 2将确定组合CDK4/6和PFKFB3的影响在体外抑制葡萄糖代谢，细胞周期，生长和生存。 AIM 3将检查代谢和药理学CDK4/6和PFKFB3抑制作用作为单疗法的生长效应以及合并体内乳腺癌的小鼠模型。我们预计我们的研究将支持PFKFB3的临床测试抑制剂与CDK4/6抑制剂结合使用，以增加晚期ER+乳腺癌患者的存活率。