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: 8282647
• 负责人: Andrean Llewela Burnett
• 金额: $ 11.38万
• 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/8282647
• 关键词: Antioxidants; Biochemical; Cancer Biology; Cell Cycle Progression; Cells; Cetuximab; Combined Modality Therapy; Defect; Deoxyglucose; Differentiation and Growth; 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; Principal Investigator; Production; Protein Tyrosine Kinase; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Pyruvate; Radiation; Radio; Reactive Oxygen Species; Receptor Signaling; Relative (related person); Research; Resistance; Respiration; Role; Signal Pathway; Signal Transduction; 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; improved; in vivo; inhibitor/antagonist; killings; mitochondrial dysfunction; neoplastic cell; overexpression; programs; receptor; therapy design; thioredoxin peroxidase; tumor; wortmannin

Program Director/Principal Investigator (Last, First, Middle): Simons, Andrean L. PROJECT SUMMARY (Seeinstructions): 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. RELEVANCE (Seeinstructions): Activation of Akt signaling is commonly observed in human head and neck cancers and induces stimulation of glycolysis. If head and neck cancer cells utilize glucose metabolism to compensate for increased metabolic production of hydroperoxides, then inhibition of glycolysis (with 2-deoxyglucose, 2DG) combined with Akt inhibitors should enhance sensitivity of cancer cells to radiation by inducing oxidative stress. This project tests the hypothesis that inhibitors of Akt/EGFR signaling can enhance 2DG-induced radio-sensitization via metabolic oxidative stress in HNSCC. The results could provide a new paradigm for designing combination therapies for improving head and neck cancer therapy.

项目主任/首席调查员(最后、第一、中间)：Simons，Andrean L. 项目总结(见说明)： PI3K/Akt通路在人头颈部癌(HNSCC)及其癌变过程中被频繁激活 已发现激活可诱导癌细胞糖酵解的剂量依赖性刺激，这是 与体内更具侵袭性的恶性肿瘤相关。癌细胞葡萄糖代谢增强 (与正常细胞相比)被认为是一种补偿机制，保护 细胞内过氧化氢是线粒体呼吸变化的副产物，通过形成 丙酮酸和NADPH。此外，葡萄糖代谢增加(通过FDG-PET测量)已经被 使用糖酵解抑制剂2-脱氧-D-葡萄糖增加对葡萄糖剥夺的敏感性 (2DG)。目前的提案验证了假设：抑制Akt/EGFR信号将显著增强 2DG通过代谢氧化应激诱导人头颈部癌细胞放化疗增敏 在体外和体内。一个也将被检验的推论是，人类的头部和大脑 在体颈部癌细胞摄取FDG可预测联合治疗的敏感性 基于抑制Akt/EGFR信号转导结合2DG的多种癌症治疗方法。目标1和目标2将 确定PI3K/Akt通路的抑制剂是否可以增强2DG诱导的放射增敏作用[即， LY294002，Perifosine，Wortmannin]和/或被认为抑制激活的化疗药物 EGFR[即厄洛替尼和西妥昔单抗]通过代谢氧化应激在人头颈部癌细胞中的表达 体外和体内。目标3将确定2DG+Akt/EGFR抑制剂是否诱导放射增敏的程度 而氧化应激可以通过FDG-PET测定的葡萄糖摄取来预测。的长期目标是 这项工作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，以开发治疗HNSCC的联合疗法 肿瘤对葡萄糖缺乏和代谢氧化应激的特异性敏感性。 相关性(请参阅说明)： Akt信号通路的激活在人类头颈癌中是常见的，并诱导刺激 糖酵解。如果头颈部癌细胞利用葡萄糖代谢来补偿增加的代谢产物 过氧化氢，那么糖酵解的抑制(用2-脱氧葡萄糖，2DG)与Akt抑制剂联合使用应该会加强 通过诱导氧化应激，癌细胞对辐射的敏感性。该项目测试了一种假说，即抑制剂 AKT/EGFR信号通路可通过代谢氧化应激增强2DG诱导的HNSCC放射增敏作用。结果是 可为设计改善头颈部癌症治疗的联合疗法提供新的范例。