Project 2: Exploiting Labile Iron Pools for Improving NSCLC Therapy Using Pharmacological Ascorbate

项目 2：利用药理学抗坏血酸利用不稳定铁池改善 NSCLC 治疗

• 批准号: 10005908
• 负责人: Douglas Robert Spitz
• 金额: $ 47.73万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005908
• 关键词: Adjuvant; Aftercare; Animal Model; Ascorbic Acid; Biochemical; Biological Markers; Cancer Patient; Carboplatin; Cell Culture Techniques; Cell Respiration; Cellular Metabolic Process; Chemosensitization; Chemotherapy and/or radiation; Clinical; Clinical Data; Clinical Trials; DNA Damage; Data; Dose; Epithelial Cells; Evaluable Disease; Excision; Ferritin; Glioblastoma; Human; Hydrogen Peroxide; In Transferrin; In Vitro; In complete remission; Infusion procedures; Intravenous; Iron; Lung; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Mediating; Metabolism; Non-Small-Cell Lung Carcinoma; Normal Cell; Operative Surgical Procedures; Oxidation-Reduction; Paclitaxel; Pancreatic Adenocarcinoma; Pathway interactions; Pharmacologic Ascorbate; Phase II Clinical Trials; Phase Ib/II Clinical Trial; Pre-Clinical Model; Predisposition; Proteins; Publishing; Radiation; Radio; Radiosensitization; Regulation; Research; Role; Safety; Stable Disease; Structure of parenchyma of lung; Superoxides; Survival Rate; TFRC gene; Testing; Toxic effect; Transferrin; Treatment Efficacy; United States; X-Ray Computed Tomography; Xenograft procedure; base; bronchial epithelium; cancer biomarkers; cancer cell; cancer therapy; chemoradiation; chemotherapy; disorder control; fluorodeoxyglucose positron emission tomography; improved; improved outcome; in vivo; innovation; iron metabolism; objective response rate; phase II trial; pre-clinical; radiation response; response; standard of care; success; uptake

Project Summary/Abstract - Project 2: Lung cancer is the second most prevalent and most lethal cancer in the United States [1]. Despite recent advances, 5-year survival has remained essentially unchanged for the last 40 years at 11-17% [2] and additional approaches are urgently needed to improve outcomes. Pharmacological ascorbate (P-AscH-; high dose intravenous vitamin C) has recently re-emerged as an agent that enhances cancer cell responses to radiation and chemotherapy in cell culture and in animal models. Preliminary data show selective toxicity as well as chemo-radiosensitization of human non-small cell lung cancer (NSCLC) versus normal non- transformed bronchial epithelial cells (HBEpC) with P-AscH- treatment. However the mechanisms underlying the differential susceptibility of lung cancer vs. normal cells to P-AscH- are not known. Based on strong pre- clinical and clinical data from an ongoing clinical trial in NSCLC, Project 2 will test the hypothesis that P-AscH- selectively sensitizes NSCLC cells to radiation and chemotherapy by 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. This hypothesis will be tested mechanistically in preclinical models in Aim 1 as well as in a phase 1B/2 clinical trial in stage III inoperable lung cancer patients in Aim 2. Aim 1 will determine in vitro and in vivo if differential regulation of redox-active labile iron pools by O2- and H2O2 causes alterations in Fe metabolism (i.e. transferrin receptor, ferritin, Fe-S proteins) that mediate P-AscH--induced radio-chemotherapy sensitization in NSCLC vs. normal lung epithelial cells. Aim 2 will determine in a phase 1b/2 clinical trial if combining P-AscH- with radiation + Carbo/Taxol can increase treatment efficacy in stage IIIA/B inoperable NSCLC subjects as determined by increases in median overall survival. Biomarkers of FDG uptake pre- and post-treatment as determined by FDG PET-CT imaging, transferrin saturation, 4HNE-modified proteins, and circulating levels of labile Fe will be determined in the clinical trial and correlated to clinical responses. The successful completion of this project will define biochemical mechanisms involving O2-/H2O2 mediated disruptions in iron metabolism underlying P-AscH--mediated selective toxicity and radio-chemo- sensitization in NSCLC vs. normal cells as well as providing a new paradigm for using P-AscH- clinically to exploit fundamental differences in cancer vs. normal cell metabolism for increasing treatment efficacy in stage IIIA/B inoperable lung cancer subjects using traditional radio-chemotherapies.

项目摘要/摘要 - 项目2： 肺癌是美国第二流行和最致命的癌症[1]。尽管最近 进步，在过去的40年中，5年生存基本上保持不变，为11-17％[2]和 迫切需要采用其他方法来改善结果。药理学抗坏血酸（P-ASCH-；高 剂量静脉内维生素C）最近重新出现为一种增强癌细胞反应的药物 细胞培养和动物模型中的放射和化学疗法。初步数据显示选择性毒性为 以及人类非小细胞肺癌（NSCLC）的化学触发性 通过P-ASCH处理转化的支气管上皮细胞（HBEPC）。但是机制的基础 肺癌与正常细胞对P-ASCH-的差异敏感性尚不清楚。基于强大的预 - NSCLC正在进行的临床试验中的临床和临床数据，项目2将检验以下假设。 通过增加癌细胞稳定的癌细胞稳定，有选择地将NSCLC细胞带入放射和化学疗法 H2O2的状态水平是由于由氧化还原活性铁代谢的特异性中断而导致的 O2/H2O2的内源水平。该假设将在AIM 1中的临床前模型中进行机械测试 以及在III期无法使用的肺癌患者中的1b/2期临床试验中，AIM 1将 确定体外和体内是否由O2和H2O2引起的氧化还原活性不稳定铁池的差异调节 Fe代谢的改变（即转铁蛋白受体，铁蛋白，Fe-S蛋白）介导P-ASCH诱导的 NSCLC与正常肺上皮细胞的射线化学疗法敏感性。 AIM 2将在一个阶段确定 1B/2临床试验如果将P-Asch-与辐射 +碳水化合物/紫杉醇相结合可以提高阶段的治疗效率 IIIA/B无法使用的NSCLC受试者由中位总生存期增加确定。 FDG的生物标志物 通过FDG PET-CT成像，转铁蛋白饱和度，4HNE修饰的摄取前和治疗后的摄取前和后处理 蛋白质和不稳定Fe的循环水平将在临床试验中确定，并与临床相关 回答。该项目的成功完成将定义涉及O2的生化机制-/H2O2 P-ASCH介导的选择性毒性和无线电化学介导的铁代谢中介导的破坏 NSCLC与正常细胞的敏化以及为在临床上使用P-Asch的新范式 利用癌症的基本差异与正常细胞代谢，以提高阶段的治疗效率 IIIA/B使用传统的放射化学疗法的肺癌受试者无法使用。