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: 8468578
• 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/8468578
• 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.

项目主管/首席研究员（后、一、中）：Simons, Andrean L。

项目成果

2-Deoxy-d-glucose Suppresses the In Vivo Antitumor Efficacy of Erlotinib in Head and Neck Squamous Cell Carcinoma Cells.

2-脱氧-D-葡萄糖抑制了厄洛替尼在头和颈部鳞状细胞癌细胞中的体内抗肿瘤功效。

• DOI: 10.3727/096504016x14586627440192
• 发表时间: 2016
• 期刊: Oncology research
• 影响因子: 3.1
• 作者: Sobhakumari A;Orcutt KP;Love-Homan L;Kowalski CE;Parsons AD;Knudson CM;Simons AL
• 通讯作者: Simons AL

NOX4 mediates cytoprotective autophagy induced by the EGFR inhibitor erlotinib in head and neck cancer cells.

• DOI: 10.1016/j.taap.2013.07.013
• 发表时间: 2013-11-01
• 期刊: TOXICOLOGY AND APPLIED PHARMACOLOGY
• 影响因子: 3.8
• 作者: Sobhakumari, Arya;Schickling, Brandon M.;Love-Homan, Laurie;Raeburn, Ayanna;Fletcher, Elise V. M.;Case, Adam J.;Domann, Frederick E.;Miller, Francis J., Jr.;Simons, Andrean L.
• 通讯作者: Simons, Andrean L.