Elucidating and exploiting NAD metabolic defects in cancer

阐明和利用癌症中的 NAD 代谢缺陷

• 批准号: 10349607
• 负责人: Collin David Heer
• 金额: $ 8.88万
• 依托单位: YALE UNIVERSITY
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10349607
• 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; Defect; 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; career; chemoradiation; chemosensitizing agent; chemotherapy; cytotoxic; experience; glucose uptake; inhibitor/antagonist; interest; lung cancer cell; 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，占全球近 占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%。鉴于这些不良结果，选择性靶向癌细胞的新治疗方法正在开发中。 迫切需要。尽管最近在癌症氧化还原代谢领域的兴趣，癌症之间的联系， 氧化还原代谢和DNA损伤修复/信号传导作为增强肿瘤细胞对 放射-化学疗法仍然在很大程度上未被探索。我的博士论文工作试图利用内在的差异 在癌细胞NAD+代谢中使癌细胞对放射-化学疗法敏感。我们假设 用烟酰胺选择性消耗NSCLC细胞中的NAD（P）（H）（相对于正常细胞） 磷酸核糖基转移酶（NAMPT）抑制剂将通过以下方式赋予有效的放射-化学-敏化作用： 诱导过氧化氢介导的代谢性氧化应激和/或细胞毒性PARP- DNA复合物。我的初步数据支持这一假设，在剩下的F99阶段，因果关系 NAMPT抑制对代谢性氧化应激的放射-化学增敏作用和/或 将建立持久的PARP 1-DNA复合物形成。我会继续调查DNA损伤 信号/修复和癌细胞氧化还原代谢作为博士后研究人员研究的关系 共济失调毛细血管扩张症突变（ATM）和失调的癌细胞氧化还原代谢之间的关系， 增强癌细胞对放射-化学疗法的反应。总的来说，我相信这个F99/K 00奖项将 为我提供手段，利用我的技能作为一个氧化还原生物学家，以建立一个研究生涯 专注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 到放射化学疗法。