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

描述（由申请人提供）：PI3K/Akt通路的激活在人类头颈癌（HNSCC）中经常被观察到，其激活在癌细胞中诱导糖酵解的剂量依赖性刺激，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，保护细胞内过氧化氢不受线粒体呼吸改变的副产物的影响，过氧化氢是通过丙酮酸和NADPH的形成而形成的。此外，葡萄糖代谢的增加（通过FDG-PET测量）与糖酵解抑制剂2-脱氧-d -葡萄糖（2DG）对葡萄糖剥夺的敏感性增加有关。目前的提案验证了以下假设：在体外和体内，抑制Akt/EGFR信号传导将显著增强2dg诱导的人头颈部癌细胞通过代谢氧化应激的放射/化学致敏。还将测试的一个推论假设是，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，将预测基于抑制Akt/EGFR信号通路结合2DG的联合癌症治疗的敏感性。目的1和2将确定是否可以通过PI3K/Akt通路抑制剂（即LY294002、perifosine、wortmannin）和/或化疗药物（即厄洛替尼和西妥昔单抗）在体外和体内通过代谢氧化应激在人头颈部癌细胞中抑制EGFR激活)增强2dg诱导的放射致敏。目的3将确定FDG-PET测定的葡萄糖摄取是否可以预测2DG+Akt/EGFR抑制剂诱导的放射致敏和氧化应激的程度。这项工作的长期目标是为使用糖酵解抑制剂提供生化基础，使用2DG， PI3K/Akt通路抑制剂和/或EGFR抑制剂，基于肿瘤对葡萄糖剥夺和代谢氧化应激的特异性敏感性，开发联合治疗方法来治疗HNSCC。

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.