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

基本信息

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
项目类别：
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

项目摘要

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.

与许多其他癌症一样，宫颈癌主要通过有氧糖酵解来代谢葡萄糖，即 Warburg 效应，这种改变的肿瘤细胞生理学可以通过 18F-氟脱氧葡萄糖-正电子成像发射断层扫描（FDG-PET）。该项目旨在检验以下假设：葡萄糖增加的肿瘤预处理 FDG-PET 成像的摄取本质上具有抗辐射性，并且这种抗辐射性可以通过以下方法逆转：利用专门针对肿瘤葡萄糖代谢的药物组合。初步数据显示 PI3K/AKT 信号传导的组成型激活可能是驱动葡萄糖异常的机制之一宫颈癌中的代谢和 PIK3CA 的激活突变与远处转移的增加有关。标准放化疗（盆腔放疗加同步放化疗）后发生转移并降低生存率顺铂化疗）。当前提案中的实验正在进行中以产生临床前支持使用 PI3K/AKT 通路抑制剂组合作为代谢放射增敏剂的数据活动性宫颈肿瘤。研究策略采用机械方法来研究 PI3K/AKT 通路宫颈癌的改变，并开发了一种新的靶向放射增敏策略，该策略结合了 AKT 信号传导抑制剂与糖酵解 (2-DG) 抑制剂。具体目标#1 的目标是确定由抑制葡萄糖代谢引起的硫醇介导的氧化应激是否有助于 PI3K/AKT 抑制使宫颈癌细胞放射增敏的机制。具体目标的目标 #2 是确定 PI3K/AKT 信号传导的改变（即突变和抑制剂）是否影响 FDG 使用新型临床相关的人类宫颈癌模型进行体内吸收和辐射反应在鼠标中。这些肿瘤可以在植入前在体外进行操作，以直接测试其功能单个基因或评估特定基因突变的影响，这将提供严格和可重复的系统来评估抑制剂组合并确定单个基因是否突变可以作为治疗反应的生物标志物。具体目标 #3 的目标是开发代谢可用于识别接受 PI3K/AKT 靶向放射增敏治疗的患者的签名抑制剂加2-DG。代谢特征的开发将采用创新方法，使用患者特异性基因组和代谢组数据的组合。如果经过验证，代谢特征 Aim 3 中开发的技术将来可用于选择接受 PI3K/AKT 抑制剂治疗的患者 +/- 2-DG 作为一种对代谢活跃和放射抗性肿瘤进行靶向放射增敏的新方法。因为 PI3K/AKT 通路的改变和葡萄糖代谢的调节在人类癌症，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。