Project 3: MRI Imaging of Redox Active Fe Predicts GBM Responses to Pharmacological Ascorbate

项目 3：氧化还原活性 Fe 的 MRI 成像预测 GBM 对药理抗坏血酸的反应

基本信息

批准号：
10240532
负责人：
Bryan Allen
金额：
$ 37.29万
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/10240532
关键词：
Adjuvant Adverse event Animal Model Animals Astrocytes Biochemical Biological Assay Biological Markers Cancer Patient Cell Respiration Cells Chelating Agents Chemotherapy and/or radiation Clinical Trials DNA Damage DNA Double Strand Break Data Dose Etiology Excision Ferritin Glioblastoma Goals Human Hydrogen Peroxide Image In Vitro Infusion procedures Intravenous Ions Iowa Iron Magnetic Resonance Imaging Malignant neoplasm of brain Malignant neoplasm of pancreas Mediating Metabolism Metals Modality Modeling Molecular Multicenter Trials Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Oxidation-Reduction Oxidative Stress Pathway interactions Patients Pharmacologic Ascorbate Pharmacology Phase Phase I Clinical Trials Plasma Predisposition Process Prognosis Proteins Publishing Radiation Radiosensitization Regulation Relaxation Research Personnel Role T2 weighted imaging Testing Toxic effect Treatment Efficacy United States Universities Xenograft Model aggressive therapy antitumor effect ascorbate brain cell cancer cell cancer therapy chemoradiation imaging approach imaging modality improved improved outcome in vivo innovation intraperitoneal iron metabolism knock-down metal chelator novel overexpression oxidative DNA damage parametric imaging patient derived xenograft model pre-clinical predicting response radiation effect relating to nervous system response success temozolomide treatment response

项目摘要

Project Summary/Abstract - Project 3: Glioblastoma multiforme (GBM) is the most common malignant brain tumor in the United States but despite the aggressive treatment GBM has a dismal prognosis with a median overall survival of ~15 months. Investigators in Project 3 have found that pharmacological ascorbate (P-AscH-), is a promising adjuvant to chemo-radiation therapy in GBM exploiting fundamental differences in oxidative metabolism. Preliminary data demonstrate the selective toxicity of P-AscH- to GBM cells, relative to normal human astrocytes (NHA), occurs via H2O2-induced oxidative stress mediated by redox active Fe ions. Furthermore, in a pre-clinical GBM model as well as in a phase 1 clinical trial (NCT01752491), they found that P-AscH- (achieving ~20 mM [plasma]) + radiation and temozolomide therapy was well-tolerated with minimal adverse events while showing encouraging therapeutic responses. Finally, preliminary data also support the idea that magnetic resonance (MR) imaging may be capable of detecting the redox state of Fe (i.e., Fe+2/Fe+3) for predicting responses to P-AscH- in combination with chemo-radiation therapy via assessing changes of T2* relaxometry. Currently, there is no clear understanding of mechanisms causing the differential susceptibility of GBM vs. normal brain cells to P-AscH- in vivo. Project 3 will test the hypothesis that P-AscH- selectively increases labile redox active Fe associated H2O2 formation in human GBM cells, relative to normal astrocytes, leading to increased oxidative DNA damage and increased sensitivity of GBM cells to radiation and temozolomide that can be assessed in vivo using MR imaging with T2* relaxometry and quantitative susceptibility mapping. Aim 1 will determine if P-AscH--induced increases in intracellular [H2O2] mediate chemo-radiosensitization in patient derived GBM cells of Proneural, Neural, Classical and Meschymal subtypes relative to normal human astrocytes (NHA) via enhanced DNA double strand breaks and differences in H2O2 metabolism in GBM cells. Aim 2 will determine if increased labile iron pools (LIP) mediate the sensitivity of GBM vs. NHA to P-AscH--induced chemo-radiosensitization. Aim 3 will determine in orthotopic GBM xenograft models if P-AscH- induced regulation of the redox-active LIP and selective sensitization to radiation and chemotherapy can be predicted using T2* MRI imaging and quantitative susceptibility mapping as well as standard biochemical assays. Completion of the aims will define biochemical mechanisms underlying P-AscH--mediated selective chemo-radiosensitization of GBM cells in vitro and in vivo orthotopic models as well as investigating highly innovative MR imaging approaches to predict responses. Project 3 is also well-integrated into the overall theme of the PO1 to provide a new paradigm for exploiting fundamental differences in redox metabolism to improve treatment efficacy in cancer patients using P-AscH-.

项目摘要/摘要 - 项目 3：多形性胶质母细胞瘤（GBM）是美国最常见的恶性脑肿瘤，但尽管积极治疗 GBM 的预后很差，中位总生存期约为 15 个月。调查员项目 3 发现药理学抗坏血酸 (P-AscH-) 是一种有前途的化疗佐剂利用氧化代谢的根本差异来治疗 GBM。初步数据表明相对于正常人星形胶质细胞 (NHA)，P-AscH- 对 GBM 细胞的选择性毒性是通过 H2O2 诱导发生的由氧化还原活性铁离子介导的氧化应激。此外，在临床前 GBM 模型以及 1 期临床试验 (NCT01752491)，他们发现 P-AscH-（达到约 20 mM [血浆]）+ 辐射和替莫唑胺治疗耐受性良好，不良事件极少，同时显示出令人鼓舞的治疗效果回应。最后，初步数据也支持这样的观点：磁共振（MR）成像可能是能够检测 Fe 的氧化还原态（即 Fe+2/Fe+3），以预测对 P-AscH- 组合的反应通过评估 T2* 弛豫测量的变化进行化学放射治疗。目前，对于导致 GBM 与 GBM 的易感性差异的机制尚无明确的了解。体内正常脑细胞转化为 P-AscH-。项目3将检验P-AscH-选择性增加的假设相对于正常星形胶质细胞，人 GBM 细胞中不稳定的氧化还原活性 Fe 相关的 H2O2 形成，导致 DNA 氧化损伤增加，GBM 细胞对辐射的敏感性增加替莫唑胺可使用 MR 成像与 T2* 弛豫测量和定量进行体内评估敏感性图。目标 1 将确定 P-AscH 诱导的细胞内 [H2O2] 增加是否介导患者来源的原神经、神经、经典和间质 GBM 细胞的化学放射增敏通过增强 DNA 双链断裂和差异，确定相对于正常人星形胶质细胞 (NHA) 的亚型 GBM 细胞中的 H2O2 代谢。目标 2 将确定增加的不稳定铁池 (LIP) 是否会介导 GBM 与 NHA 对 P-AscH 诱导的化学放射增敏的敏感性。目标 3 将在原位确定 GBM 异种移植模型如果 P-AscH 诱导氧化还原活性 LIP 的调节和选择性敏化可以使用 T2* MRI 成像和定量磁敏感图来预测放疗和化疗以及标准生化测定。目标的完成将定义生化机制潜在的 P-AscH 介导的 GBM 细胞体外和体内原位选择性化学放射增敏作用模型以及研究高度创新的 MR 成像方法来预测反应。项目3是也很好地融入了 PO1 的总体主题，为利用基本原理提供了新的范式氧化还原代谢的差异可提高使用 P-AscH- 的癌症患者的治疗效果。