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

• 批准号: 10430005
• 负责人: YOANNIS IMBERT-FERNANDEZ
• 金额: $ 35.69万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-09 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10430005
• 关键词: 6-Phosphofructo-2-kinase; 6-Phosphofructokinase; Attenuated; Automobile Driving; Binding; 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; Growth; In Vitro; Malignant Neoplasms; Mediating; Metabolic; Metastatic breast cancer; Oncogenic; Oral; Pathway interactions; Patients; Pharmacology; Phase; Phase I/II Trial; Phosphorylation; Progression-Free Survivals; Relapse; Resistance; Resistance development; Retinoblastoma Protein; Role; Testing; Time; advanced breast cancer; base; blood glucose regulation; cancer cell; combinatorial; cyclin D3; 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; prevent; rational design; research clinical testing; response; targeted treatment; therapy resistant; treatment response; tumor

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的致癌机制，即细胞周期蛋白D1绕过CDK 4/6抑制 导致6-磷酸果糖-2-激酶（PFKFB 3）和葡萄糖代谢的刺激。的目的 建议描述PFKFB 3在介导对CDK 4/6抑制的适应或抵抗以及对CDK 4/6抑制的适应或抵抗中的作用 确定提高CDK 4/6抑制剂疗效的新方法，以实现持久的反应， IV期HR+乳腺癌患者。雌激素受体（ER）-细胞周期蛋白D1-CDK 4/6通路的失调是 ER+乳腺癌的标志，促进了CDK 4/6抑制剂的开发。虽然 对ER+晚期乳腺癌患者给予CDK 4/6抑制剂， 在无进展生存期的改善中，几乎所有患者不变地随着时间发展耐药性和复发。 CDK 4/6抑制后葡萄糖代谢的激活变得越来越明显。一个关键的刺激因素， 糖酵解是PFKFB 3酶，其合成果糖2，6-二磷酸（F2，6 BP），一种有效的变构剂， 限速6-磷酸果糖-1-激酶（PFK 1）的激活剂。F2，6 BP控制整个过程中的通量 糖酵解途径，因此是癌细胞增殖所必需的。在初步研究中，我们 提供证据表明，在ER+乳腺癌中，PFKFB 3表达和活性响应于CDK 4抑制而增加。 癌细胞和乳腺癌患者肿瘤。值得注意的是，我们发现PFKFB 3抑制剂PFK-158， 抗CDK 4靶向治疗的体内外抗肿瘤活性。我们假设PFKFB 3是一个 细胞周期蛋白D1-CDK 4/6轴的基本调节效应物，通过以下方式减弱CDK 4/6抑制作用 刺激葡萄糖代谢。此外，我们假设，遗传或药理学抑制， PFKFB 3将通过使细胞丧失维持足够的细胞周期的能力来增加CDK 4/6抑制剂的功效。 葡萄糖代谢是生存和生长所必需的。目的1将确定CDK 4/6 抑制诱导PFKFB 3表达。目的2将确定CDK 4/6和PFKFB 3组合的作用。 抑制体外糖代谢、细胞周期、生长和存活。目标3将检查代谢和 药理学CDK 4/6和PFKFB 3抑制作为单一疗法和联合治疗的生长作用 小鼠体内乳腺癌模型。我们预计，我们的研究将支持PFKFB 3的临床试验 抑制剂与CDK 4/6抑制剂组合以增加晚期ER+乳腺癌患者的存活。