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

基本信息

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
项目类别：
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

项目摘要

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：尽管近年来肺癌是美国第二大流行和最致命的癌症[1]。随着技术的进步，过去 40 年的 5 年生存率基本保持在 11-17% 不变 [2] 迫切需要其他方法来改善结果。剂量静脉注射维生素 C）最近作为一种增强癌细胞反应的药物重新出现。细胞培养和动物模型中的放射和化疗的初步数据显示选择性毒性。以及人类非小细胞肺癌 (NSCLC) 与正常非小细胞肺癌 (NSCLC) 的化学放射增敏作用然而，P-AscH 治疗转化的支气管上皮细胞 (HBEpC) 的机制如下。肺癌与正常细胞对 P-AscH- 的敏感性差异尚不清楚。来自正在进行的 NSCLC 临床试验的临床和临床数据，项目 2 将检验以下假设：P-AscH- 通过增加癌细胞的稳定性，选择性地使 NSCLC 细胞对放疗和化疗敏感。由于氧化还原活性铁代谢的特定破坏而导致 H2O2 的状态水平 O2●-/H2O2 的内源水平将在目标 1 的临床前模型中进行机械测试。以及目标 2 中针对 III 期不可手术肺癌患者的 1B/2 期临床试验。目标 1 将在体外和体内确定 O2●- 和 H2O2 对氧化还原活性不稳定铁库的差异调节是否会导致介导 P-AscH 诱导的 Fe 代谢（即转铁蛋白受体、铁蛋白、Fe-S 蛋白）的改变 NSCLC 与正常肺上皮细胞的放化疗敏感性目标 2 将在一个阶段确定。 1b/2临床试验如果P-AscH-与放疗+Carbo/Taxol相结合可以提高阶段治疗效果 IIIA/B 不能手术的 NSCLC 受试者通过 FDG 中位总生存期的增加来确定。治疗前和治疗后的摄取通过 FDG PET-CT 成像、转铁蛋白饱和度、4HNE 修饰确定蛋白质和不稳定铁的循环水平将在临床试验中确定，并与临床相关该项目的成功完成将确定涉及 O2-/H2O2 的生化机制。介导的 P-AscH 介导的铁代谢破坏 - 介导的选择性毒性和放射化学 - NSCLC 与正常细胞的致敏性，并为临床上使用 P-AscH- 提供新的范例利用癌症与正常细胞代谢的根本差异来提高阶段治疗效果 IIIA/B 无法手术的肺癌受试者使用传统的放化疗。