Redox manipulation of iron to improve glioblastoma therapy: A phase 1 trial

铁的氧化还原操作可改善胶质母细胞瘤治疗：1 期试验

基本信息

批准号：
10651509
负责人：
Bryan Allen
金额：
$ 21.81万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-16 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651509
关键词：
Ascorbic Acid Astrocytes Biochemical Biological Markers Brain Cell Death Chemistry Chemotherapy and/or radiation Clinical Clinical Trials Complement DNA DNA Damage Data Dependence Deposition Development Diagnosis Dose Dose Limiting Edema Electrons Enrollment Excision FDA approved Future Glioblastoma Glioma Hour Human Hydrogen Peroxide Hydroxyl Radical Image Imaging Techniques In Vitro Incidence Infusion procedures Intervention Intravenous infusion procedures Ionizing radiation Iron Iron Overload Iron deficiency anemia Lipids MGMT gene Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of pancreas Maps Mediating Metabolism Metals Methylation Molecular No Evidence of Disease Non-Small-Cell Lung Carcinoma Normal Cell Normal tissue morphology Operative Surgical Procedures Outcome Ovarian Oxidation-Reduction Oxygen Patients Pharmacologic Ascorbate Phase Phase I Clinical Trials Phase II Clinical Trials Plasma Pre-Clinical Model Predisposition Prognosis Prognostic Marker Progression-Free Survivals Proteins Radiation Radiation therapy Reaction Recurrence Relaxation Research Research Project Grants Superoxides Supplementation T2 weighted imaging Testing Therapeutic Time Toxic effect Treatment Protocols Tumor Tissue United States anticancer research ascorbate cancer cell cancer imaging cancer therapy chemoradiation chemotherapy early phase clinical trial efficacy evaluation ferumoxytol first-in-human imaging biomarker improved in vivo individual patient innovation iron oxide iron oxide nanoparticle iron supplementation liver injury mutational status nanoparticle non-invasive imaging novel novel strategies oxidation phase 2 study phase I trial phase II trial pre-clinical promoter response standard care standard of care superparamagnetism synergism temozolomide treatment response tumor

项目摘要

Project Summary & Abstract Glioblastoma (GBM) is a deadly primary brain cancer with a median overall survival (OS) of only 14-16 months. Despite a treatment regimen including surgical resection followed by radio-chemo-therapy, the majority of patients will recur within 7 months of diagnosis. We identified in a phase 1 trial that pharmacological ascorbate (PAscH-; IV vitamin C reaching ≈ 20 mM in plasma) combined with standard GBM therapy is well tolerated with promising outcomes in poor prognosis subjects with MGMT positive/IDH1 wild type tumors. This led to the recent completion of enrollment of a PAscH- GBM phase 2 trial (NCT02344355) treated with standard radiation and temozolamide and PAscH-. Median OS in the GBM phase 2 trial was 22 months. Our research team made the exciting mechanistic observation that PAscH- selectively enhances GBM radio- chemo-therapy, relative to normal human astrocytes, because of differences in the metabolism of redox active iron (Fe). This mechanism results from the selective increased Fe-mediated oxidation of ascorbate in tumor tissue leading to the formation of hydrogen peroxide (H2O2). H2O2 can be directly toxic to cancer cells or can react with Fe through Fenton chemistry to produce hydroxyl radicals that damage DNA, proteins, and lipids and hence synergizes with radio-chemo-therapy. Furthermore, preliminary analysis of the PAscH- GBM phase 2 trial identified that subjects with increased tumor Fe, detected by magnetic resonance imaging (MRI) T2* relaxation, had significantly increased progression free survival (11.2 months vs. 5.7 months). This suggests T2* relaxation may be a non-invasive biomarker to predict Fe dependent response to PAscH-. Ferumoxotyol (FMX) is an Fe oxide nanoparticle used in glioma MR imaging. Preliminary pre-clinical data show that ascorbate and ionizing radiation facilitate the release of Fe from FMX that can be detected by alterations in MRI parameters (T1 enhancement and decreased T2* relaxation time). The released Fe would then be available for the therapeutic enhancement of PAscH-. In GBM human tumors, FMX mediated T1 enhancement detects Fe release for up to 72 hours after infusion in the tumor and surrounding edema volume. Given this exciting preliminary data, FMX may represent the ideal GBM imaging and therapy agent when combined with PAscH-. We hypothesize iron supplementation with FMX in combination with PAscH- and standard of care therapy will be safe and increase redox active Fe content (detected by T2* relaxation) in GBM tumors as part of a phase 1 clinical trial. Each subject’s GBM tumor will be analyzed by T2* MRI for changes in redox active Fe as well as assessing plasma for evidence of Fe overload and liver injury. Completion of these studies will assess the impact of the redox active Fe manipulation on GBM therapy. If successful, future phase 2 studies will investigate the potential of combining PAscH- and FMX with standard GBM therapy to improve survival and sensitize subjects that might not otherwise respond to PAscH- radio- chemo-therapy.

项目总结及摘要胶质母细胞瘤 (GBM) 是一种致命的原发性脑癌，中位总生存期 (OS) 仅为 14-16 尽管采取了包括手术切除和放化疗在内的治疗方案，但我们在 1 期试验中发现，大多数患者会在诊断后 7 个月内复发。抗坏血酸（PAscH-；血浆中 IV 维生素 C 达到 ≈ 20 mM）与标准 GBM 治疗相结合效果良好 MGMT 阳性/IDH1 野生型肿瘤预后不良的受试者可耐受并获得有希望的结果。导致最近完成了一项 PAscH-GBM 2 期试验 (NCT02344355) 的入组 GBM 2 期试验中的中位 OS 为 22 个月。我们的研究团队进行了令人兴奋的机制观察，即 PAscH- 选择性增强 GBM 放射- 化疗，相对于正常人星形胶质细胞，由于氧化还原活性代谢的差异这种机制是由于肿瘤中铁介导的抗坏血酸氧化选择性增加所致。导致过氧化氢（H2O2）形成的组织可以直接毒害癌细胞或可以。通过芬顿化学与 Fe 发生反应，产生羟基自由基，从而损害 DNA、蛋白质和脂质因此与放化疗具有协同作用。此外，PAscH-GBM 阶段的初步分析。 2 项试验发现，通过磁共振成像 (MRI) T2* 检测到的受试者肿瘤铁含量增加放松，显着增加了无进展生存期（11.2 个月 vs. 5.7 个月）。 T2* 松弛可能是预测 PAscH- 的 Fe 依赖性反应的非侵入性生物标志物。 Ferumoxotyol (FMX) 是一种用于神经胶质瘤 MR 成像的铁氧化物纳米颗粒。表明抗坏血酸和电离辐射促进 FMX 中 Fe 的释放，可通过以下方法检测： MRI 参数的改变（T1 增强和 T2* 弛豫时间减少）。然后可用于 FMX 介导的 T1 在 GBM 人类肿瘤中增强 PAscH- 的治疗作用。增强可检测肿瘤和周围水肿体积输注后长达 72 小时的 Fe 释放。鉴于这些令人兴奋的初步数据，FMX 可能代表理想的 GBM 成像和治疗剂我们勇敢地补充了 FMX 与 PAscH- 的组合。标准护理治疗将是安全的并增加氧化还原活性铁含量（通过 T2* 弛豫检测）作为 1 期临床试验的一部分，每位受试者的 GBM 肿瘤将通过 T2* MRI 进行分析。氧化还原活性铁的变化以及评估血浆中铁过载和肝损伤的证据。这些研究的完成将评估氧化还原活性铁操作对 GBM 治疗的影响。成功的未来 2 期研究将调查将 PAscH- 和 FMX 与标准相结合的潜力 GBM 治疗可提高生存率并提高可能对 PAscH 没有反应的受试者的敏感性化疗。