Exploiting Redox Metabolism Using Pharmacological Ascorbate for Cancer Therapy

项目摘要/摘要--总体： 这一极具创新性的研究计划将调查药理抗坏血酸(P-Asch-.高- 剂量，静脉注射维生素C)在癌症治疗中。静脉注射抗坏血酸，而不是口服抗坏血酸， 产生较高的血浆浓度(15-20 mM)，其范围是选择性的细胞毒性到 癌细胞。我们高度整合的翻译研究团队的研究表明，P-Asch- 选择性地诱导胰腺、肺和肺组织的氧化应激和细胞毒性以及放化疗敏感性。 脑癌与正常细胞。同时进行的胰腺癌、脑癌和肺癌的临床试验 计划P-Asch-已被证明与标准护理无线电相结合是安全和耐受性良好的- 化疗。我们已经在我们的所有模型系统中坚定地建立了P-Asch-是一种用于递送的亲药物 过氧化氢(过氧化氢)。这些结果导致了一个重要的假设，即变异的癌细胞 氧化代谢失调调节不稳定的氧化还原活性金属离子池促进P-Asch氧化形成 过氧化氢。本计划项目申请的总体主题是P-Asch-可以作为一种轻松的 可实施的临床辅助传统的放化疗，将选择性地针对癌症与。 正常细胞通过增加过氧化氢的形成。此外，这一机制似乎广泛适用于 几种癌症。本申请将这些原则应用于高度集成的方法、机制、 P-Asch-1在胰腺癌治疗中的应用 (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所有方面。这个 生物标记物核心(核心B)将通过提供所有P-Asch剂量的确认与所有三个项目进行互动 临床试验对象和临床前模型以及支持测量和分子 体内和体外氧化应激标志物、氧化还原活性金属和抗氧化酶的处理。 临床试验核心(核心C)将协调临床试验中的所有努力，包括受试者的应计费用， 数据管理、监管监督和报告。圆满完成这一拟议方案项目 将在氧化还原的补充方法中展示易于实施的新范式的可行性 利用P-Asch进行基于新陈代谢的癌症治疗，这可能为大规模第三阶段奠定基础 多机构合作分组试行。由于该方法的基础是针对 癌组织和正常组织中P-Asch-的氧化还原生化/代谢，这些研究也有 展示功能成像和氧化还原敏感生物标记物是否可以提供一个强大的平台 预测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-.