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.

项目摘要和摘要胶质母细胞瘤（GBM）是一种致命的原发性脑癌，中位总生存率（OS）仅为14-16 月份。尽管采用了治疗方案，包括手术切除，然后进行无线电治疗，但大多数患者将在诊断后的7个月内复发。我们在第1阶段试验中确定了药物抗坏血酸（Pasch-; IV维生素C达到≈20毫米等离子体）与标准GBM治疗结合很好 MGMT阳性/IDH1野生型肿瘤的预后不良受试者的承诺耐受性。这导致最近完成了Pasch-GBM 2期试验（NCT02344355）的入学率标准辐射，替莫唑胺和帕斯奇。 GBM 2期试验中的中位OS为22个月。我们的研究团队对Pasch进行了令人兴奋的机械观察，有选择地增强了GBM Radio-Radio- 相对于正常人星形胶质细胞的化学疗法，由于氧化还原活性的代谢差异铁（Fe）。这种机制是由肿瘤中抗坏血酸的Fe介导的氧化的选择性增加而产生的组织导致形成过氧化氢（H2O2）。 H2O2可以直接对癌细胞有毒，也可以通过Fenton化学与FE反应，产生羟基自由基，损害DNA，蛋白质和脂质因此，与放射化疗疗法协同作用。此外，Pasch-GBM相的初步分析 2试验确定，通过磁共振成像（MRI）T2*检测到肿瘤Fe增加的受试者放松，无进展生存率显着增加（11.2个月比5.7个月）。这暗示着 T2*松弛可能是一种非侵入性生物标志物，可以预测FE依赖于Pasch-的反应。铁莫索醇（FMX）是用于神经胶质瘤MR成像的Fe氧化物纳米颗粒。初步临床前数据证明抗坏血酸和电离辐射有助于从FMX中释放Fe MRI参数的改变（T1增强和降低T2*松弛时间）。发行的FE将然后可用于pasch-的治疗性增强。在GBM人类肿瘤中，FMX介导的T1 增强在肿瘤和周围水肿体积中输注后最多72小时检测Fe释放。鉴于此令人兴奋的初步数据，FMX可能代表理想的GBM成像和治疗剂结合帕施 - 。我们假设用FMX与Pasch-和Pasch-和护理疗法将是安全的，并且会增加氧化还原活性FE含量（通过T2*检测）在GBM肿瘤中，作为1期临床试验的一部分。每个受试者的GBM肿瘤将通过T2* MRI分析氧化还原活性FE的变化以及评估血浆的FE超负荷和肝损伤的证据。这些研究的完成将评估氧化还原主动操纵对GBM治疗的影响。如果成功的未来第2阶段研究将研究将Pasch和FMX与标准组合的潜力 GBM治疗以提高可能对Pasch- Radio-Radio-Radio-Radio-Radio-Radio-Radio-Radio-Radio- 化学疗法。