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: 10478857
• 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/10478857
• 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 Melissa Fath 博士目前获得题为“利用氧化还原”的计划项目拨款的 100% 支持 使用药理学抗坏血酸（P-AscH−）进行癌症治疗的代谢”（P01 CA217797）的主题。 该 P01 正在利用药理学抗坏血酸（P-AscH-；高剂量 P01由3个主要研究项目和3个项目组成。 该提案高度集成，专注于临床前、转化和临床研究。 与 P-AscH− 在癌症治疗中的使用相关，Fath 博士的研究将影响所有三项研究 该 R50 申请建议为 Fath 博士提供 100% 的薪资支持，以支持所有项目。 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 当前提案的单位主任 Douglas Spitz 博士是多方合作的一部分。 PI领导团队以及项目2“利用不稳定铁池改善 具体而言，P01 中的项目 2 将检验该假设。 P-AscH− 通过选择性地使非小细胞肺癌对放疗和化疗敏感 由于氧化还原活性铁的特定破坏，癌细胞稳态 H2O2 水平增加 由内源性水平的 O2.-/H2O2 介导的新陈代谢。 自由基和放射生物学计划。 爱荷华大学放射肿瘤学系（FRRBP）是一个理想的科学环境 对于这项拟议的研究，因为其历史根源于辐射生物学以及自由基理论 Spitz 博士是 FRRBP 的部门主任。 Fath 博士是一名副研究科学家，十多年来一直是一名积极的合作成员。 Fath 博士在测试自由基、硫醇氧化、氧化还原敏感性的参与方面拥有丰富的专业知识 许多利用氧化还原操作的研究中的信号传导、途径和氧化损伤终点 她在临床药学方面的背景和培训， 药物和天然产品化学以及自由基癌症生物学使她非常适合在 这个高度协作和综合的团队进行体外和体内转化研究以及 Fath 博士将重点关注 O2·- 和 H2O2 的氧化还原生物学以及参与。 Fe 代谢在介导 P-AscH 诱导的放化疗增敏中的不同作用。 她将量化放射化学敏化、测量稳态 H2O2、研究和实验室操纵铁 使用药理学和遗传学方法进行池化，并评估氧化应激和 DNA 损伤 此外，Fath 博士将负责测量癌症治疗模型中的生物标志物。 临床试验中的氧化应激并确定它们是否与临床反应相关很明显，博士。 Fath 的经验和专业知识对于 P01 CA217797 来说非常宝贵，她完全有资格成为 P01 CA217797 的候选人。 P50奖励机制。