OPTIMIZING RADIATION THERAPY THROUGH MANIPULATION OF TUMOR GLUCOSE METABOLISM

宫颈癌，像许多其他癌症一样，主要通过有氧糖酵解代谢葡萄糖，即，的 瓦尔堡效应，并且这种改变的肿瘤细胞生理学可以通过18 F-氟脱氧葡萄糖-正电子探针成像。 发射断层扫描（FDG-PET）。该项目旨在验证一个假设，即肿瘤与葡萄糖增加 在预处理FDG-PET成像上的摄取是固有的放射抗性，并且这种放射抗性可以通过以下方式逆转： 利用专门针对肿瘤葡萄糖代谢的药物组合。初步数据显示， PI 3 K/AKT信号传导的组成性激活可能是驱动异常葡萄糖的一种机制， 宫颈癌中的代谢，以及PIK 3CA中的激活突变与宫颈癌的远处转移增加相关。 标准化放疗（盆腔放疗加同期化疗）后， 顺铂化疗）。正在进行当前提案中的实验，以产生临床前 数据支持使用PI 3 K/AKT通路抑制剂组合作为代谢的放射增敏剂 活动性宫颈肿瘤本研究采用机理研究的方法对PI 3 K/AKT通路进行研究 宫颈癌的改变，并开发了一种新的靶向放射增敏策略， AKT信号传导抑制剂与糖酵解抑制剂（2-DG）。具体目标#1的目的是 确定由葡萄糖代谢抑制引起的硫醇介导的氧化应激是否有助于 PI 3 K/AKT抑制使宫颈癌细胞放射增敏的机制。具体目标的目的 #2是确定PI 3 K/AKT信号传导的改变（即，突变和抑制剂）影响FDG 通过使用新的临床相关的人宫颈癌模型在体内的摄取和辐射反应 在老鼠。这些肿瘤可以在植入前在体外操作，以直接测试肿瘤细胞的功能。 单个基因或评估特定基因突变的影响，这将提供一个严格的， 可重复的系统，以评估抑制剂组合，并确定是否个别基因突变 可以作为治疗反应的生物标志物。具体目标#3的目标是开发一种代谢 可用于识别PI 3 K/AKT靶向放射增敏治疗患者的特征 抑制剂加2-DG。代谢特征的开发将采用创新的方法， 患者特异性基因组学和代谢组学数据的组合。如果得到验证，代谢特征 在目标3中开发的方法可以在未来用于选择用PI 3 K/AKT抑制剂+/-治疗的患者 2-DG作为代谢活性和放射抗性肿瘤的靶向放射增敏的新方法。 由于PI 3 K/AKT通路的改变和葡萄糖代谢的调节在糖尿病患者中很常见， 人类癌症，这项研究的结果有可能改善许多其他癌症的放射治疗结果。 癌症，包括乳腺癌、子宫癌、胰腺癌和前列腺癌。

Cervical cancer, like many other cancers, metabolizes glucose primarily through aerobic glycolysis, i.e., the Warburg effect, and this altered tumor cell physiology can be imaged by 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET). This project is designed to test the hypothesis that tumors with increased glucose uptake on pretreatment FDG-PET imaging are inherently radio-resistant, and this radio-resistance can be reversed by taking advantage of drug combinations that specifically target tumor glucose metabolism. Preliminary data has shown that constitutive activation of PI3K/AKT signaling may be one mechanism that drives aberrant glucose metabolism in cervical cancer, and activating mutations in PIK3CA are associated with increased distant metastasis and decreased survival outcome after standard chemoradiation (pelvic irradiation plus concurrent cisplatin chemotherapy). The experiments in the current proposal are being performed to generate preclinical data in support of using PI3K/AKT pathway inhibitor combinations as radio-sensitizers for metabolically active cervical tumors. The research strategy employs a mechanistic approach to study PI3K/AKT pathway alterations in cervical carcinoma and develops a novel strategy for targeted radio-sensitization that combines an inhibitor of AKT signaling with an inhibitor of glycolysis (2-DG). The objective of Specific Aim #1 is to determine if thiol-mediated oxidative stress caused by inhibition of glucose metabolism contributes to the mechanism by which PI3K/AKT inhibition radio-sensitizes cervical cancer cells. The objective of Specific Aim #2 is to determine whether alterations in PI3K/AKT signaling (i.e., mutations and inhibitors) affect FDG uptake and the radiation response in vivo by using a novel, clinically relevant model of human cervical cancer in the mouse. These tumors can be manipulated in vitro prior to implantation to directly test the function of individual genes or to evaluate the effects of specific gene mutations, which will provide a rigorous and reproducible system to evaluate inhibitor combinations and to determine whether individual gene mutations can serve as biomarkers for response to treatment. The objective of Specific Aim #3 is to develop a metabolic signature that can be used to identify patients for treatments with targeted radio-sensitization with PI3K/AKT inhibitors plus 2-DG. Development of the metabolic signature will employ an innovative approach using a combination of patient-specific genomic and metabolomic data. If validated, the metabolic signature developed in Aim 3 could be used in the future to select patients for treatment with PI3K/AKT inhibitors +/- 2-DG as a novel approach for targeted radio-sensitization of metabolically active and radio-resistant tumors. Because alterations in the PI3K/AKT pathway and the regulation of glucose metabolism are common in human cancer, the results of this research have the potential to improve radiotherapy outcome for many other cancers including tumors of the breast, uterus, pancreas and prostate.