Repurposing redox active agents for exploiting differences in cancer cell metabolism for improving cancer therapy

重新利用氧化还原活性剂，利用癌细胞代谢的差异来改善癌症治疗

• 批准号: 10239057
• 负责人: Melissa Ann Fath
• 金额: $ 15.51万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-17 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10239057
• 关键词: Ascorbic Acid; Award; Biological Markers; Biology; Cancer Biology; Chemosensitization; Chemotherapy and/or radiation; Clinical; Clinical Research; Clinical Trials; Core Facility; DNA Damage; Dose; Environment; Free Radicals; Funding; Glioblastoma; Grant; Hydrogen Peroxide; In Vitro; Intravenous; Ions; Iowa; Iron; Leadership; Lung; Malignant Neoplasms; Measures; Mediating; Melissa; Metabolic; Metabolism; Metals; Modeling; Natural Products Chemistry; Non-Small-Cell Lung Carcinoma; Normal Cell; Oxidation-Reduction; Oxidative Stress; Pharmacologic Ascorbate; Pharmacology; Pharmacy facility; Plant Roots; Postdoctoral Fellow; Program Research Project Grants; Radiation Oncology; Radio; Radiobiology; Research; Research Personnel; Research Project Grants; Scientist; Signal Pathway; Sulfhydryl Compounds; Testing; Toxic effect; Training; Translational Research; Universities; Wages; Work; ascorbate; cancer cell; cancer therapy; chemoradiation; drug repurposing; experience; genetic approach; improved; in vivo; iron metabolism; knowledge base; member; novel; oxidation; oxidative damage; pancreatic cancer cells; preclinical study; programs; radiation response; response; theories; translational study; tumor metabolism

Abstract Dr. Melissa Fath is currently 100% supported by the program project grant entitled “Exploiting Redox Metabolism Using Pharmacological Ascorbate (P-AscH−) for Cancer Therapy” (P01 CA217797). The theme of this P01 is exploiting cancer cell redox metabolism using pharmacological ascorbate (P-AscH-; high dose intravenous vitamin C) for improving cancer therapy. The P01 is composed of 3 major research projects and 3 core facilities. The proposal is highly integrated and focused on preclinical, translational and clinical studies relevant to the use of P-AscH− in cancer therapy and Dr. Fath's research will impact all three of the research projects and two of the cores. This R50 application proposes 100 % salary support for Dr. Fath to support all the projects and two cores in the P01 research program as well as any new research initiatives funded by NCI that may arise from that work. The Unit Director of the current proposal, Dr. Douglas Spitz, is part of the multi- PI leadership team as well as the principle investigator on Project 2, “Exploiting Labile Iron Pools for Improving NSCLC Therapy Using Pharmacological Ascorbate”. Specifically Project 2 in the P01 will test the hypothesis that P-AscH− selectively sensitizes non-small cell lung cancers to radiation and chemotherapy by selectively increasing cancer cell steady-state levels of H2O2 as a result of specific disruptions in redox-active iron metabolism mediated by endogenous levels of O2.-/H2O2 . The Free Radical and Radiation Biology Program (FRRBP) in the Department of Radiation Oncology at the University of Iowa is an ideal scientific environment for this proposed research because of its historic roots in radiation biology as well as the free radical theory of cancer in association with a strong Radiation Oncology Department. Dr. Spitz is the division director of FRRBP and Dr. Fath is an associate research scientist that has been an active collaborative member for over 10 years. Dr. Fath has considerable expertise in testing the involvement of free radicals, thiol oxidation, redox sensitive signaling pathways, and oxidative damage end-points in many studies exploiting manipulations of redox metabolism to repurpose drugs for cancer therapy. Her background and training in Clinical Pharmacy, Medicinal & Natural Products Chemistry, and Free Radical Cancer Biology make her ideally suited to work in this highly collaborative and integrated group doing both in vitro and in vivo translational research as well as supporting clinical trials. Dr. Fath will focus on the redox biology of O2·- and H2O2 as well as the involvement of Fe metabolism in the differential effects of that mediate P-AscH- induced radio-chemotherapy sensitization. She will quantify radio-chemo- sensitization, measure steady-state H2O2, study and manipulate labile iron pools using both pharmacological and genetic approaches, and assess oxidative stress, and DNA damage endpoints in cancer treatment models. In addition, Dr. Fath will be responsible for measuring biomarkers of oxidative stress in the clinical trials and determining if they correlate to clinical responses. It is clear that Dr. Fath's experience and expertise is invaluable to P01 CA217797 and she is well-qualified as a candidate for the P50 award mechanism.

抽象的 梅利莎·法斯（Melissa Fath）博士目前由计划项目赠款100％支持，名为“利用氧化还原 使用药理学抗坏血酸（P-ASCH-）进行癌症治疗的代谢”（P01 CA217797）。 该p01正在使用药物抗坏血酸（P-ASCH-；高剂量）利用癌细胞氧化还原代谢 静脉内维生素C）改善癌症治疗。 P01由3个主要研究项目和3个组成 核心设施。该提案高度整合，并集中于临床前，翻译和临床研究 与使用P-ASCH-在癌症治疗和FATH博士的研究中有关的所有三项研究都将 项目和两个核心。这份R50申请提案为FATH博士提供100％的薪水支持，以支持所有人 P01研究计划中的项目和两个核心以及NCI资助的任何新研究计划 这可能是由于这项工作而产生的。当前建议的单位主任道格拉斯·斯皮兹（Douglas Spitz）博士是多人的一部分 PI领导团队以及项目2的主要调查员，“利用迷宫池来改进 NSCLC使用药理学抗坏血酸”。特别是P01中的项目2将检验假设 P-Asch选择性地将非小细胞肺癌感知到放射线和化学疗法。 由于氧化还原活性铁的特异性破坏，增加了H2O2的癌细胞稳态水平 由内源性的O2介导的代谢。-/H2O2。自由基和辐射生物学计划 （FRRBP）爱荷华大学的放射线肿瘤学系是理想的科学环境 对于这项拟议的研究，由于其在辐射生物学上的历史根源以及自由基理论 癌症与强大的辐射肿瘤学系联合。 Spitz博士是FRRBP的部门主任 Fath博士是一位副研究科学家，已有10多年的积极合作成员。 Fath博士考虑了测试自由基，硫代氧化物，氧化还原敏感的专业知识 在许多研究氧化还原操纵的研究中，信号通路和氧化损伤终点 代谢复制用于癌症治疗的药物。她在临床药房的背景和培训， 药物和天然产品化学和自由基癌症生物学使她非常适合从事 这个高度协作和综合的小组在体外和体内翻译研究以及 支持临床试验。 Fath博士将重点介绍O2·和H2O2的氧化还原生物学以及参与 Fe代谢在介导P-ASCH诱导的放射化学疗法敏感性的差异作用中。 她将量化对无线电化学敏感的，测量稳态H2O2，研究和操纵不稳定的铁 使用药物和遗传方法的池，评估氧化应激以及DNA损伤 癌症治疗模型中的终点。此外，Fath博士将负责测量 临床试验中的氧化应激，并确定它们是否与临床反应相关。显然博士 Fath的经验和专业知识对于P01 CA217797非常宝贵，她是合格的候选人 P50奖励机制。