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

摘要 梅丽莎·法特博士目前100%得到了名为《利用氧化还原》的项目拨款的支持 使用药理抗坏血酸(P-Asch−)进行癌症治疗的代谢“(P01CA217797)。的主题 这个P01使用药理抗坏血酸(P-Asch-；高剂量)来开发癌细胞的氧化还原代谢 静脉注射维生素C)，以改善癌症治疗。P01由3个主要研究项目和3个 核心设施。该提案高度整合，侧重于临床前、转化性和临床研究。 与P-Asch−在癌症治疗中的使用有关，法特博士的研究将影响这三项研究 项目和两个核心。这个R50应用程序建议为Dr.Fath提供100%的工资支持，以支持所有 P01研究计划中的项目和两个核心以及由NCI资助的任何新的研究倡议 在这项工作中可能出现的问题。目前提议的单位主任道格拉斯·斯皮茨博士是多项- PI领导团队以及项目2“开发不稳定的铁矿以改善环境”的首席调查员 使用药理抗坏血酸治疗非小细胞肺癌“。具体地说，P01中的项目2将检验假设 P-Asch−选择性增敏非小细胞肺癌的实验研究 氧化还原活性铁的特定破坏导致癌细胞稳态过氧化氢水平增加 代谢受内源O2.-/H2O2水平的调节。自由基与辐射生物学计划 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，因为它的历史根源是辐射生物学，以及 癌症与强放射肿瘤科有关。斯皮茨博士是FRRBP的部门主任 法特博士是一名副研究科学家，10多年来一直是活跃的合作成员。 Fath博士在测试自由基、硫醇氧化、氧化还原敏感性方面拥有相当的专业知识 许多利用氧化还原操作的研究中的信号通路和氧化损伤终点 新陈代谢以重新调整癌症治疗药物的用途。她在临床药剂学方面的背景和训练， 药物和天然产品化学和自由基癌症生物学使她非常适合在 这个高度合作和整合的小组在体外和体内进行翻译研究，以及 支持临床试验。法特博士将重点研究O2·-和H2O2的氧化还原生物学，以及 铁代谢在介导P-Asch诱导放化疗增敏中的差异性作用。 她将量化放射化学敏感性，测量稳定状态的过氧化氢，研究和操作不稳定的铁 使用药理学和遗传学方法，并评估氧化应激和DNA损伤 癌症治疗模式的终结点。此外，法特博士还将负责测量 临床试验中的氧化应激，并确定它们是否与临床反应相关。很明显，Dr。 Fath的经验和专业知识对P01 CA217797来说是无价的，她完全有资格成为 P50奖励机制。

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.