OPTIMIZING RADIATION THERAPY THROUGH MANIPULATION OF TUMOR GLUCOSE METABOLISM

通过控制肿瘤葡萄糖代谢优化放射治疗

• 批准号: 8613756
• 负责人: Julie Kristina Schwarz
• 金额: $ 31.63万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8613756
• 关键词: AKT inhibition; AKT1 gene; Affect; Aftercare; Antioxidants; Biological Markers; Biopsy; Breast; Cancer Patient; Cancer cell line; Cell Death; Cell Proliferation; Cell physiology; Cervical; Cervix Neoplasms; Cervix carcinoma; Cisplatin; Clinical; Couples; DNA Damage; Data; Deoxyglucose; Development; Distant Metastasis; Drug Combinations; Epidermal Growth Factor Receptor; Exhibits; Future; Gene Mutation; Genes; Genomics; Glucose; Glucose Transporter; Glycolysis; Human; Image; In Vitro; Individual; Inferior; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mammary Neoplasms; Measurement; Mediating; Medicine; Metabolic; Metabolism; Methods; Modeling; Mus; Mutation; Neoplasm Metastasis; Outcome; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; PI3K/AKT; PIK3CA gene; PTEN gene; Pancreas; Pathway interactions; Patients; Pelvis; Phenotype; Phosphorylation; Physiology; Process; Prostate; Proto-Oncogene Proteins c-akt; Radiation; Radiation therapy; Radio; Radioresistance; Regulation; Research; Research Design; Resistance; Role; Sampling; Serum; Signal Transduction; Site; Sulfhydryl Compounds; Survival Analysis; System; Testing; Tumor Bank; Up-Regulation; Uterus; Warburg Effect; aerobic glycolysis; base; cancer cell; cancer therapy; cell transformation; chemoradiation; chemotherapy; clinically relevant; cytotoxic; cytotoxicity; deprivation; design; fluorodeoxyglucose positron emission tomography; glucose metabolism; glucose uptake; hexokinase; human FRAP1 protein; implantation; improved; in vivo; inhibitor/antagonist; innovation; irradiation; metabolomics; mouse model; neoplastic cell; new therapeutic target; next generation sequencing; novel; novel strategies; oncology; pre-clinical; prospective; public health relevance; research study; response; treatment response; tumor; uptake

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.

像许多其他癌症一样，宫颈癌主要通过有氧糖酵解，即，即 Warburg效应，这种改变的肿瘤细胞生理可以通过18F-氟脱氧葡萄糖 - 蛋白质成像 排放断层扫描（FDG-PET）。该项目旨在测试葡萄糖增加的肿瘤的假设 对预处理FDG-PET成像的吸收本质上是耐热性的，并且这种抗性可以通过 利用专门针对肿瘤葡萄糖代谢的药物组合。初步数据已显示 PI3K/AKT信号的本构激活可能是一种驱动异常葡萄糖的机制 宫颈癌的代谢和PIK3CA的激活突变与远处增加有关 标准化学放疗后转移和生存结果降低（骨盆辐射加并发 顺铂化疗）。当前建议中的实验正在进行生成临床前 支持使用PI3K/AKT途径抑制剂组合作为代谢的无线电灵敏度的数据 活性宫颈肿瘤。该研究策略采用一种机械方法来研究PI3K/AKT途径 宫颈癌的改变，并制定了一种新颖的靶向无线电敏化策略 具有糖酵解抑制剂（2-DG）的AKT信号传导的抑制剂。特定目的1的目的是 确定硫醇介导的氧化应激是否因抑制葡萄糖代谢引起的氧化应激有助于 PI3K/AKT抑制无线敏感性宫颈癌细胞的机制。特定目标的目的 ＃2是确定PI3K/AKT信号传导（即突变和抑制剂）的改变是否影响FDG 通过使用一种新型人类宫颈癌的临床相关模型，体内摄取和辐射反应 在鼠标中。这些肿瘤可以在植入之前在体外进行操纵，以直接测试 单个基因或评估特定基因突变的影响，这将提供严格的和 可再现的系统评估抑制剂组合并确定单个基因突变是否 可以用作对治疗的反应的生物标志物。特定目的3的目的是发展代谢 可用于识别患有PI3K/AKT靶向无线敏化治疗的患者的签名 抑制剂加2-DG。代谢签名的开发将采用一种创新的方法 患者特异性基因组和代谢组数据的组合。如果得到验证，则代谢签名 将来可以使用AIM 3中开发的AIM 3选择患者用于PI3K/AKT抑制剂+/- 2-DG作为代谢活性和抗射电肿瘤的靶向射击敏感性的新方法。 因为PI3K/AKT途径的改变和葡萄糖代谢的调节很常见 人类癌症，这项研究的结果有可能改善许多其他 包括乳房，子宫，胰腺和前列腺的肿瘤在内的癌症。