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

项目主任/主要研究者（最后，第一，中间）：西蒙斯，安德烈L。 项目总结（见说明）： PI3K/Akt通路的激活在人头颈癌（HNSCC）中经常观察到， 已经发现激活诱导癌细胞中糖酵解的剂量依赖性刺激， 与体内更具侵袭性的恶性肿瘤有关癌细胞中葡萄糖代谢增加 （与正常细胞相比）被认为是一种补偿机制， 细胞内氢过氧化物作为改变线粒体呼吸的副产物通过形成 丙酮酸盐和NADPH。此外，葡萄糖代谢增加（通过FDG-PET测量）已被证实。 与使用糖酵解抑制剂2-脱氧-D-葡萄糖对葡萄糖剥夺的敏感性增加相关 （2DG）。目前的提议测试了以下假设：抑制Akt/EGFR信号传导将显著增强 2DG通过代谢氧化应激诱导人头颈癌细胞的放/化疗增敏作用 在体外和体内。一个必然的假设，也将被测试的是，在何种程度上，人类的头部和 通过PET成像确定的颈部癌细胞体内摄取FDG将预测对联合化疗的敏感性。 基于抑制Akt/EGFR信号传导与2DG组合的方式癌症疗法。目标1和2将 确定2DG诱导的放射增敏是否可以通过PI3K/Akt途径的抑制剂增强[即， LY294002、哌立福辛、渥曼青霉素]和/或化疗剂，这些化疗剂被认为能够抑制 EGFR [即，埃罗替尼和西妥昔单抗]在人头颈癌细胞中通过代谢性氧化应激作用， 体外和体内。目的3将确定2DG + Akt/EGFR介导的放射增敏程度 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 本研究的目的是为糖酵解抑制剂的应用提供一个生物化学理论基础，使用2DG，PI3K/Akt 途径抑制剂和/或EGFR抑制剂，以开发联合方式治疗HNSCC， 肿瘤对葡萄糖剥夺和代谢性氧化应激的特异性敏感性。 相关性（参见说明）： Akt信号传导的激活通常在人头颈癌中观察到，并诱导Akt信号传导的刺激。 糖酵解如果头颈癌细胞利用葡萄糖代谢来补偿增加的代谢产物 那么抑制糖酵解（用2-脱氧葡萄糖，2DG）与Akt抑制剂组合应增强 通过诱导氧化应激增强癌细胞对辐射的敏感性。该项目测试的假设，抑制剂的 Akt/EGFR信号转导可通过代谢性氧化应激增强2DG诱导的HNSCC放射增敏作用。结果 可以为设计用于改善头颈癌治疗的联合疗法提供新的范例。

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.