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药理学抗坏血酸（P-AscH-）的使用。 剂量、静脉注射维生素 C) 治疗癌症。静脉注射抗坏血酸，但不口服抗坏血酸， 产生高血浆浓度（15-20 mM），该浓度在选择性细胞毒性范围内 癌细胞。我们高度整合的转化研究团队的研究表明，P-AscH- 选择性诱导胰腺、肺和胰腺的氧化应激和细胞毒性以及放射化疗增敏 脑癌与正常细胞。在我们的并行正在进行的胰腺癌、脑癌和肺癌临床试验中 P-AscH- 计划与护理标准无线电结合时已被证明是安全且耐受性良好的 化疗。我们在所有模型系统中都牢固地确立了 P-AscH- 是一种前药，用于递送 过氧化氢（H2O2）。这些结果得出了一个总体假设：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 双氧水。该计划项目应用程序的总体主题是 P-AscH- 可以轻松用作 传统放化疗的可实施临床辅助剂，将选择性地针对癌症而不是癌症。 正常细胞通过增加 H2O2 的形成。此外，该机制似乎广泛适用于 几种癌症。当前的应用程序将这些原则应用于高度集成的方法、机制、 使用 P-AscH- 作为辅助剂治疗胰腺导管腺癌的生物标志物 （PDAC，项目 1）、非小细胞肺癌（NSCLC，项目 2）和多形性胶质母细胞瘤（GBM，项目 3）。行政核心（核心 A）将协调项目和生物统计分析的各个方面。这 生物标志物核心（核心 B）将通过提供所有 P-AscH 剂量的确认来与所有三个项目进行互动。 临床试验受试者和临床前模型以及支持测量和分子 体外和体内氧化应激标记物、氧化还原活性金属和抗氧化酶的操作。 临床试验核心（核心 C）将协调临床试验中的所有工作，包括受试者的招募、 数据管理、监管监督和报告。成功完成本拟议计划项目 将证明在氧化还原补充方法中易于实施的新范例的可行性 利用 P-AscH- 的基于代谢的癌症治疗可为大规模 3 期临床试验奠定基础 多机构合作小组试验。由于该方法是基于针对根本差异 癌症与正常组织中 P-AscH- 的氧化还原生物化学/代谢，这些研究还具有 有潜力证明功能成像和氧化还原敏感生物标志物是否可以提供强大的平台 预测对 P-AscH- 的治疗反应。