Use of 2-deoxy-D-glucose & PI3K/Akt pathway inhibitors in head & neck cancer ther

2-脱氧-D-葡萄糖的用途

• 批准号: 7849720
• 负责人: Andrean Llewela Burnett
• 金额: $ 11.14万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849720
• 关键词: Antioxidants; Biochemical; Cancer Biology; Cell Cycle Progression; Cells; Cetuximab; Combined Modality Therapy; Defect; Deoxyglucose; Dose; Drug Metabolic Detoxication; Electrons; Energy Metabolism; Enzymes; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Exhibits; Family; Glucose; Glucosephosphate Dehydrogenase; Glycolysis; Glycolysis Inhibition; Goals; Head; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human; Hydrogen Peroxide; In Vitro; Ionizing radiation; Laboratories; Lead; Malignant Neoplasms; Measures; Mediating; Metabolic; Metabolism; Mitochondria; NADP; Natural regeneration; Normal Cell; Oxidative Stress; Oxygen; Pathway interactions; Pentose Phosphate Cycle Pathway; Pentoses; Perifosine; Peroxidases; Peroxides; Phosphotransferases; Play; Positron-Emission Tomography; Pre-Clinical Model; Predisposition; Production; Protein Tyrosine Kinase; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Pyruvate; Pyruvates; Radio; Reactive Oxygen Species; Receptor Signaling; Relative (related person); Research; Resistance; Respiration; Role; Signal Pathway; Solid Neoplasm; Source; Superoxides; Testing; Therapeutic Agents; Therapeutic Intervention; Work; angiogenesis; base; cancer cell; cancer therapy; cell growth; cell transformation; chemotherapeutic agent; combined cancer modality therapy; cytotoxicity; deprivation; design; glucose metabolism; glucose uptake; glutathione peroxidase; in vivo; inhibitor/antagonist; killings; mitochondrial dysfunction; neoplastic cell; overexpression; receptor; therapy design; thioredoxin peroxidase; tumor; wortmannin

DESCRIPTION (provided by applicant): Activation of the PI3K/Akt pathway is observed frequently in human head and neck cancer (HNSCC) and its activation has been found to induce a dose-dependent stimulation of glycolysis in cancer cells, which correlates with a more aggressive malignancy in vivo. Increased glucose metabolism in cancer cells (compared to normal cells) is believed to function as a compensatory mechanism protecting from intracellular hydroperoxides formed as byproducts of altered mitochondrial respiration via the formation of pyruvate and NADPH. Furthermore, increased glucose metabolism (measured by FDG-PET) has been associated with increased sensitivity to glucose deprivation using the glycolytic inhibitor 2-deoxy-D-glucose (2DG). The current proposal tests the hypotheses: Inhibition of Akt/EGFR signaling will significantly enhance 2DG-induced radio-/chemo-sensitization via metabolic oxidative stress in human head and neck cancer cells in vitro and in vivo. A corollary hypothesis that will also be tested is that the extent to which human head and neck cancer cells in vivo take up FDG as determined by PET imaging will predict sensitivity to combined modality cancer therapies based on inhibition of Akt/EGFR signaling combined with 2DG. Aims 1 and 2 will determine if 2DG-induced radio-sensitization can be enhanced by inhibitors of the PI3K/Akt pathway [i.e., LY294002, perifosine, wortmannin] and/or chemotherapeutic agents believed to inhibit the activation of EGFR [i.e., erlotinib and cetuximab] in human head and neck cancer cells via metabolic oxidative stress in vitro and in vivo. Aim 3 will determine if the extent of 2DG+Akt/EGFR inhibitor-induced radio-sensitization and oxidative stress can be predicted by glucose uptake as determined by FDG-PET. The long term goal of this work is to provide a biochemical rationale for the use of glycolytic inhibitors, using 2DG, PI3K/Akt pathway inhibitors and/or EGFR inhibitors, to develop combined modality therapies to treat HNSCC based on tumor specific sensitivity to glucose deprivation and metabolic oxidative stress.

描述(申请人提供)：PI3K/Akt通路的激活在人类头颈癌(HNSCC)中经常被观察到，它的激活被发现在癌细胞中诱导剂量依赖的糖酵解刺激，这与体内更具侵袭性的恶性肿瘤相关。癌细胞中葡萄糖代谢的增加(与正常细胞相比)被认为是一种代偿机制，通过丙酮酸和NADPH的形成，保护细胞内免受线粒体呼吸变化的副产物--细胞内过氧化氢的影响。此外，葡萄糖代谢增加(通过FDG-PET测量)与使用糖酵解抑制剂2-脱氧-D-葡萄糖(2DG)的葡萄糖剥夺的敏感性增加有关。目前的方案验证了以下假设：在体外和体内，抑制Akt/EGFR信号将显著增强2DG通过代谢氧化应激在人头颈部癌细胞中诱导的放化疗敏感性。还将测试的一个必然假设是，通过PET成像确定的人类头颈部癌细胞在体内摄取FDG的程度将预测基于Akt/EGFR信号抑制结合2DG的联合方式癌症治疗的敏感性。AIMS 1和2将确定PI3K/Akt通路的抑制剂[即LY294002，Perifosine，wortmannin]和/或化疗药物在体外和体内通过代谢氧化应激抑制人头颈部癌细胞中EGFR[即erlotinib和西妥昔单抗]的激活，是否可以增强2DG诱导的放射增敏。目的3将确定2DG+Akt/EGFR抑制剂诱导的放射敏化和氧化应激的程度是否可以通过FDG-PET测定的葡萄糖摄取来预测。这项工作的长期目标是为糖酵解抑制剂的使用提供生化基础，使用2DG、PI3K/Akt途径抑制剂和/或EGFR抑制剂，开发基于肿瘤对葡萄糖剥夺和代谢氧化应激的特异性敏感性的联合治疗方案。