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

描述（由申请人提供）：在人头颈癌（HNSCC）中经常观察到PI 3 K/Akt通路的激活，并且已发现其激活诱导癌细胞中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。据信癌细胞中葡萄糖代谢的增加（与正常细胞相比）作为一种补偿机制发挥作用，保护免受作为改变的线粒体呼吸的副产物通过形成丙酮酸和NADPH而形成的细胞内氢过氧化物的影响。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）的葡萄糖剥夺敏感性增加有关。目前的建议测试的假设：Akt/EGFR信号的抑制将显着增强2DG诱导的放射/化学增敏通过代谢氧化应激在人头颈癌细胞在体外和体内。还将测试的推论假设是，通过PET成像确定的人头颈癌细胞体内摄取FDG的程度将预测对基于Akt/EGFR信号传导抑制与2DG组合的联合模式癌症治疗的敏感性。目的1和2将确定2DG诱导的放射增敏是否可以通过PI 3 K/Akt途径的抑制剂增强[即，LY 294002、哌立福辛、渥曼青霉素]和/或被认为抑制EGFR活化的化疗剂[即，埃罗替尼和西妥昔单抗]在人头颈癌细胞中通过体外和体内代谢氧化应激的作用。目的3将确定是否可以通过FDG-PET测定的葡萄糖摄取来预测2DG+Akt/EGFR激动剂诱导的放射增敏和氧化应激的程度。这项工作的长期目标是提供使用糖酵解抑制剂的生物化学原理，使用2DG、PI 3 K/Akt通路抑制剂和/或EGFR抑制剂，以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模式疗法来治疗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.