Exploiting Redox Metabolism Using Pharmacological Ascorbate for Cancer Therapy

项目概要/摘要-总体： 这个高度创新的研究计划将调查使用药理抗坏血酸（P-AscH-。表示“高”之义 剂量，静脉注射维生素C）治疗癌症。静脉注射抗坏血酸，而不是口服抗坏血酸， 产生高血浆浓度（15-20 mM），其在选择性细胞毒性的范围内， 癌细胞我们高度整合的翻译研究团队的研究表明，P-AscH- 选择性诱导氧化应激和细胞毒性以及胰腺、肺和 脑癌与正常细胞的对比。在我们正在进行的胰腺癌、脑癌和肺癌临床试验中， 计划P-AscH-已被证明是安全和良好的耐受性时，与护理标准的无线电- 化疗我们已经在我们所有的模型系统中牢固地建立了P-AscH-是一种用于递送 过氧化氢（H2 O2）。这些结果导致了一个总体假设，即异常的癌细胞 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 过氧化氢这个程序项目应用程序的总体主题是，P-AscH-可以作为一个容易使用 其将选择性地靶向癌症vs. 增加H2 O2的形成。此外，这一机制似乎广泛适用于 几种癌症。本申请将这些原理应用于高度集成的方法、机制 P-AscH-作为辅助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）。 3）。行政核心（核心A）将协调项目和生物统计分析的所有方面。的 生物标志物核心（核心B）将通过在所有项目中提供P-AscH给药的确认，与所有三个项目相互作用。 临床试验受试者和临床前模型，以及支持测量和分子 在体外和体内操纵氧化应激、氧化还原活性金属和抗氧化酶的标记物。 临床试验核心（核心C）将协调临床试验中的所有工作，包括受试者招募， 数据管理、监管监督和报告。圆满完成本项目的立项工作 将证明一个容易实施的新范例的可行性，在互补的方法，以氧化还原 利用P-AscH的基于代谢的癌症治疗-这可以为大规模的第三阶段提供基础 多机构合作组试验。由于这一方法的基础是针对 P-AscH-在癌症与正常组织中的氧化还原生物化学/代谢，这些研究还具有 有可能证明功能成像和氧化还原敏感的生物标志物是否可以提供一个强大的平台， 预测对P-AscH-的治疗反应。

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-.