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

基本信息

批准号：
8074830
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
项目类别：
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/8074830
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 Production Protein Tyrosine Kinase Protein-Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Pyruvate 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

项目摘要

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（由申请人提供）：在人头和颈部癌（HNSCC）中经常观察到PI3K/AKT途径的激活，并且已经发现其激活诱导癌细胞中剂量依赖性糖酵解的刺激，这与Vivo中更具侵略性的恶性肿瘤相关。据信，癌细胞中葡萄糖代谢增加（与正常细胞相比）起作用，是一种补偿机制，可通过丙酮酸和NADPH的形成，可避免通过形成线粒体呼吸改变的细胞内氢过氧化物。此外，使用糖酵解抑制剂2-脱氧-D-葡萄糖（2DG），增加的葡萄糖代谢（通过FDG-PET测量）与对葡萄糖剥夺的敏感性增加有关。当前的提案检验假设：抑制AKT/EGFR信号传导将通过人头和颈部癌细胞的体外和体内代谢氧化应激显着增强2DG诱导的无线电/化学敏感性。还将测试的推论假设是，通过PET成像确定的人体头和颈部癌细胞在体内服用FDG的程度将预测基于抑制AKT/EGFR信号的抑制，将其敏感性敏感性。目的1和2将通过PI3K/AKT途径的抑制剂（即LY294002，Perifosine，Wortmannnin）和/或化学治疗剂的抑制剂来确定2DG诱导的无线电敏化是否可以增强。体外和体内。 AIM 3将确定2DG+AKT/EGFR抑制剂诱导的无线电敏化和氧化应激是否可以通过FDG-PET确定的葡萄糖摄取来预测。这项工作的长期目标是为使用2DG，PI3K/AKT途径抑制剂和/或EGFR抑制剂提供生物化学理由，以使用糖酵解抑制剂，从而开发合并的模态疗法，以基于肿瘤特异性敏感性治疗HNSCC，以治疗HNSCC，以对肿瘤特异性敏感性和粘液性氧化应力。