Exploiting Redox Metabolism Using Pharmacological Ascorbate for Cancer Therapy

利用药理抗坏血酸的氧化还原代谢进行癌症治疗

• 批准号: 10240529
• 负责人: Joseph J Cullen
• 金额: $ 194.32万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240529
• 关键词: Address; Adjuvant; Ascorbic Acid; Astrocytes; Biochemistry; Biological Markers; Biological Models; Biometry; Cancer Patient; Cell Respiration; Cells; Chemosensitization; Clinical; Clinical Data; Clinical Trials; DNA Damage; Data; Development; Disease; Dose; Epithelial Cells; Ferritin; Foundations; Functional Imaging; Generations; Glioblastoma; Human; Hydrogen Peroxide; Image; In Transferrin; In Vitro; Intravenous; Ions; Iowa; Iron; Lung; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Measurement; Mediating; Metabolism; Metals; Molecular; Non-Small-Cell Lung Carcinoma; Normal Cell; Normal tissue morphology; Oral; Outcome; Oxidation-Reduction; Oxidative Stress; Paclitaxel; Pancreatic Ductal Adenocarcinoma; Patients; Pharmacologic Ascorbate; Pharmacology; Phase; Placebos; Plasma; Pre-Clinical Model; Prediction of Response to Therapy; Prodrugs; Proteins; Radiation; Radio; Reactive Oxygen Species; Regulation; Reporting; Research; Serum; TFRC gene; Testing; Therapeutic; Toxic effect; Translational Research; Treatment Efficacy; Universities; anti-cancer; anticancer activity; antioxidant enzyme; ascorbate; base; cancer cell; cancer clinical trial; cancer therapy; cancer type; catalase; chemoradiation; conventional therapy; cytotoxic; cytotoxicity; data management; efficacy outcomes; epithelial to mesenchymal transition; gemcitabine; hypoxia inducible factor 1; improved; in vivo; innovation; interest; neoplastic cell; oxidation; phase II trial; phase III trial; pre-clinical; primary endpoint; programs; randomized trial; response; standard of care; therapeutically effective; tumor

Project Summary/Abstract - Overall: This highly innovative research program will investigate the use of pharmacologic ascorbate (P-AscH-. high- dose, IV delivery of vitamin C) in the treatment of cancer. Intravenous ascorbate, but not oral ascorbate, produces high plasma concentrations (15-20 mM), which are in the range that are selectively cytotoxic to cancer cells. Studies from our highly integrated translational research team have demonstrated that P-AscH- selectively induces oxidative stress and cytotoxicity as well as radio-chemo-sensitization in pancreas, lung, and brain cancer vs. normal cells. In parallel ongoing pancreas, brain, and lung cancer clinical trials within our program P-AscH- has been shown to be safe and well-tolerated when combined with standard of care radio- chemo-therapies. We have firmly established in all our model systems that P-AscH- is a pro-drug for delivery of hydrogen peroxide (H2O2). These results have led to the overarching hypothesis that aberrant cancer cell oxidative metabolism dysregulates labile redox active metal ion pools enhancing P-AscH- oxidation to form H2O2. The overall theme of this Program Project application is that P-AscH- can be used as an easily implementable clinical adjuvant to conventional radio-chemo-therapies that will selectively target cancer vs. normal cells by increasing H2O2 formation. Furthermore, this mechanism appears to be broadly applicable to several cancers. The current application applies these principles to highly integrated approaches, mechanisms, and biomarkers in the use of P-AscH- as an adjuvant in to the treatment of pancreatic ductal adenocarcinoma (PDAC, Project 1), non-small cell lung cancer (NSCLC, Project 2), and glioblastoma multiforme (GBM, Project 3). The Administrative Core (Core A) will coordinate all aspects of the project and bio-statistical analysis. The Biomarkers Core (Core B) will interact with all three projects by providing confirmation of P-AscH- dosing in all clinical trial subjects and in preclinical models as well as supporting the measurement and molecular manipulation of markers of oxidative stress, redox active metals, and antioxidant enzymes in vitro and in vivo. The Clinical Trails Core (Core C) will coordinate all the efforts in the clinical trials including accrual of subjects, data management, regulatory oversight, and reporting. Successful completion of this proposed program project will demonstrate the feasibility of an easily implemented new paradigm in complementary approaches to redox metabolism-based cancer therapy utilizing P-AscH- that could provide the foundation for large scale phase 3 multi-institutional cooperative group trials. Since the approach is based on targeting fundamental differences in the redox biochemistry/metabolism of P-AscH- in cancer vs. normal tissues, these studies also have the potential to demonstrate if functional imaging and redox sensitive biomarkers can provide a robust platform for predicting therapeutic responses to P-AscH-.

项目摘要/摘要 - 总体： 这项高度创新的研究计划将研究使用药理学抗坏血酸（P-Asch-。高 - 剂量，IV递送维生素c）在癌症治疗中。静脉注射抗坏血酸，但不是口服抗坏血酸盐， 产生高血浆浓度（15-20毫米），在选择性地细胞毒性的范围内 癌细胞。我们高度综合的翻译研究团队的研究表明，P-Asch- 有选择地诱导氧化应激和细胞毒性，以及胰腺，肺和 脑癌与正常细胞。在我们的持续胰腺，大脑和肺癌临床试验中 p-asch-的程序已被证明是安全且耐受性的，当 化学治疗。我们已经在所有模型系统中牢固确立了P-Asch-是用于交付 过氧化氢（H2O2）。这些结果导致了一个总体假设，即异常癌细胞 氧化代谢失调不稳定的氧化还原活性金属离子池增强p-asch-氧化形成形成 H2O2。该计划项目应用程序的总体主题是P-Asch-可以轻松使用 可以选择性地针对癌症的常规放射性化治疗方法可实施的临床佐剂。 正常细胞通过增加H2O2的形成。此外，这种机制似乎广泛适用于 几种癌症。当前的应用程序将这些原理应用于高度集成的方法，机制， 和生物标志物在使用P-Asch-作为胰腺导管腺癌治疗的辅助物 （PDAC，项目1），非小细胞肺癌（NSCLC，项目2）和多形胶质母细胞瘤（GBM，Project 3）。行政核心（核心A）将协调项目的所有方面和生物统计分析。这 生物标志物核心（核心B）将通过提供所有三个项目的互动 临床试验受试者和临床前模型，并支持测量和分子 在体外和体内操纵氧化应激，氧化还原活性金和抗氧化酶的标记。 临床跟踪核心（核心C）将协调临床试验中的所有努力，包括受试者的应计， 数据管理，监管监督和报告。成功完成该建议的计划项目 将证明在氧化还原的互补方法中易于实施的新范式的可行性 基于代谢的癌症疗法利用P-ASCH-可以为大规模第3期提供基础 多机构合作小组试验。由于该方法基于针对的基本差异 P-Asch-在癌症与正常组织中的氧化还原生物化学/代谢，这些研究也具有 潜力证明功能成像和氧化还原敏感的生物标志物是否可以为 预测对P-ASCH-的治疗反应。