Selective targeting of tumor cell redox metabolism and DNA damage responses to enhance cancer therapy

选择性靶向肿瘤细胞氧化还原代谢和 DNA 损伤反应以增强癌症治疗

• 批准号: 10020964
• 负责人: Collin David Heer
• 金额: $ 3.18万
• 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: 2019-09-20 至 2021-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020964
• 关键词: Accounting; Adenosine; Award; Biology; Biomedical Research; Cell Death; Cells; Cessation of life; Chemosensitization; Complex; DNA; DNA Damage; DNA Repair; DNA-Directed DNA Polymerase; Data; Diagnosis; Doctor of Philosophy; Effectiveness; Enzymes; Exhibits; Faculty; Glucose; Glutathione; Goals; Hydrogen Peroxide; Institution; Investigation; Knowledge; Link; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metabolic; Metabolism; Modality; NADP; Non-Small-Cell Lung Carcinoma; Normal Cell; Operative Surgical Procedures; Outcome; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Pentosephosphate Pathway; Pharmacology; Phase; Poly(ADP-ribose) Polymerases; Polymers; Positioning Attribute; Postdoctoral Fellow; Pre-Clinical Model; Property; Radiation therapy; Radio; Reactive Oxygen Species; Research; Research Personnel; Research Project Grants; Ribose; Role; Signal Pathway; Signal Transduction; Source; Survival Rate; System; TXN gene; Toxic effect; Training; Work; antioxidant enzyme; ataxia telangiectasia mutated protein; cancer cell; cancer therapy; career; chemoradiation; chemosensitizing agent; chemotherapy; cytotoxic; experience; glucose uptake; inhibitor/antagonist; interest; metabolic phenotype; neoplastic cell; nicotinamide phosphoribosyltransferase; overexpression; repaired; response; skills; tumor; tumor metabolism

Project Summary Lung cancer is the most commonly diagnosed and deadliest cancer in the world, accounting for over nearly one-fifth of all cancer deaths in 2018, and the 5-year survival rate for non-small cell lung cancer (NSCLC) is only 18.1%. Given these poor outcomes, new treatment approaches that selectively target cancer cells are urgently needed. Despite the recent interest in the field of cancer redox metabolism, the link between cancer redox metabolism and DNA damage repair/signaling as a means by which to enhance tumor cell responses to radio-chemotherapies remains largely unexplored. My Ph.D. thesis work seeks to exploit inherent differences in cancer cell NAD+ metabolism to sensitize cancer cells to radio-chemo-therapies. We hypothesize that selective depletion of NAD(P)(H) in NSCLC cells (versus normal cells) with nicotinamide phosphoribosyltransferase (NAMPT) inhibitors will confer potent radio-chemo-sensitization by inducing hydroperoxide-mediated metabolic oxidative stress and/or persistence of cytotoxic PARP- DNA complexes. My preliminary data supports this hypothesis and, in the remaining F99 phase, a causal link between the radio-chemo-sensitizing effects of NAMPT inhibition on metabolic oxidative stress and/or persistent PARP1-DNA complex formation will be established. I will continue by investigating DNA damage signaling/repair and cancer cell redox metabolism as a post-doctoral researcher studying the relationship between ataxia telangiectasia mutated (ATM) and dysregulated cancer cell redox metabolism with the goal of enhancing cancer cell responses to radio-chemotherapies. Overall, I believe that this F99/K00 award will provide the means for me to utilize my skills as a redox biologist in order to establish a research career focused on the role of cancer cell redox metabolism and DNA damage repair/signaling in tumor cell responses to radio-chemotherapies.

项目摘要 肺癌是世界上最常见和最致命的癌症，占近 2018年所有癌症死亡人数的五分之一，非小细胞肺癌(NSCLC)的5年生存率为 只有18.1%。考虑到这些糟糕的结果，选择性针对癌细胞的新治疗方法是 急需之物。尽管最近人们对癌症氧化还原代谢领域感兴趣，但癌症之间的联系 氧化还原代谢和DNA损伤修复/信号转导作为增强肿瘤细胞对 放射化疗在很大程度上仍未被探索。我的博士论文工作试图利用内在的差异 在癌细胞的NAD+代谢中，使癌细胞对放化疗敏感。我们假设 烟酰胺对NSCLC细胞(与正常细胞相比)NAD(P)(H)的选择性耗竭 磷酸核糖转移酶(NAMPT)抑制剂将通过以下方式实现有效的放化疗增敏 诱导过氧化氢介导的代谢氧化应激和/或细胞毒性PARP- DNA复合体。我的初步数据支持这一假设，在剩余的F99阶段，存在因果联系 NAMPT抑制代谢氧化应激的放化增敏作用与/或 将建立持久的PARP1-DNA复合体形成。我会继续调查DNA损伤 信号/修复与癌细胞氧化还原代谢关系的博士后研究 在共济失调毛细血管扩张突变(ATM)和癌细胞氧化还原代谢失调之间，目标是 增强癌细胞对放化疗的反应。总体而言，我相信这个F99/K00奖项将 为我提供手段，利用我作为氧化还原生物学家的技能来建立研究事业 着重于癌细胞氧化还原代谢和DNA损伤修复/信号在肿瘤细胞反应中的作用 去做放射化疗。