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

• 批准号: 10005909
• 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
• 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/10005909
• 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; 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; outcome forecast; overexpression; oxidative DNA damage; parametric imaging; pre-clinical; predicting response; radiation effect; relating to nervous system; response; success; temozolomide; treatment response

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： 胶质母细胞瘤多形（GBM）是美国最常见的恶性脑肿瘤 积极的治疗GBM的预后较为沮丧，总体存活率中位数约为15个月。调查人员 在项目3中发现，药理学抗坏血酸（P-ASCH-）是化学辐射的有前途的辅助药 在GBM中的治疗，利用氧化代谢的基本差异。初步数据证明了 P-ASCH-对GBM细胞的选择性毒性相对于正常的人星形胶质细胞（NHA），是通过H2O2诱导的 氧化应激由氧化还原活性FE离子介导。此外，在临床前GBM模型中以及 第1阶段临床试验（NCT01752491），他们发现P-Asch-（达到约20毫米[等离子体]） +辐射和辐射 Temozolomide疗法的耐受性良好，最小的不良事件表现出令人鼓舞的治疗 回答。最后，初步数据还支持磁共振（MR）成像可能是 能够检测Fe的氧化还原态（即Fe+2/Fe+3），以预测组合中对P-Asch-的响应 通过评估T2*弛豫计的变化，进行化学辐射疗法。 当前，尚无清楚的理解，导致GBM V的差异敏感性。 正常的脑细胞与体内p-asch-。项目3将测试P-Asch选择性增加的假设 与正常星形胶质细胞相对于正常的星形胶质细胞，不稳定的氧化还原活性Fe相关的H2O2形成 导致氧化性DNA损伤增加并增加GBM细胞对辐射和 可以使用T2*弛豫和定量的MR成像在体内评估的替莫唑胺 敏感映射。 AIM 1将确定p-asch是否诱导细胞内[H2O2]介导 胸腔，神经，经典和中腔的患者衍生的GBM细胞中的化学触觉敏化 亚型通过增强的DNA双链断裂和差异相对于正常人星形胶质细胞（NHA） 在GBM细胞中的H2O2代谢中。 AIM 2将确定增加不稳的铁池（唇）是否介导 GBM与NHA对P-ASCH的敏感性 - 诱导的化学触觉敏感性。 AIM 3将在原位性中确定 GBM异种移植模型如果P-ASCH诱导的氧化还原活性唇的调节和选择性敏化对 可以使用T2* MRI成像和定量敏感性映射来预测放射和化学疗法 以及标准的生化测定。目的的完成将定义生化机制 基本的P-ASCH介导的GBM细胞的选择性化学触发性在体外和体内原位 模型以及研究高度创新的MR成像方法以预测响应。项目3是 也融入了PO1的整体主题，以提供新的范式来利用基本 使用P-ASCH-的氧化还原代谢的差异以提高癌症患者的治疗功效。