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

项目概要和摘要 胶质母细胞瘤（GBM）是一种致命的原发性脑癌，中位总生存期（OS）仅为14-16 个月尽管治疗方案包括手术切除，然后进行放射化疗， 大多数患者会在确诊后7个月内复发。我们在一期试验中发现， 抗坏血酸（PAscH-; IV维生素C在血浆中达到1020 mM）与标准GBM治疗联合使用， 在具有MGMT阳性/IDH 1野生型肿瘤的预后不良受试者中耐受，具有有希望的结果。这 导致最近完成了PAscH-GBM 2期试验（NCT 02344355）的入组， 标准辐射和替莫唑胺和PASCH-。GBM II期试验的中位OS为22个月。 我们的研究小组进行了令人兴奋的机制观察，PAscH-选择性增强GBM无线电- 化疗，相对于正常的人星形胶质细胞，因为在氧化还原活性的代谢的差异， 铁（Fe）。这一机制的结果是选择性增加铁介导的氧化抗坏血酸在肿瘤 组织导致过氧化氢（H2 O2）的形成。H2 O2可以直接对癌细胞有毒， 通过芬顿化学与铁反应，产生破坏DNA、蛋白质和脂质的羟基自由基 并因此与放射-化学-治疗协同作用。此外，初步分析了PAscH-GBM相 2项试验确定，通过磁共振成像（MRI）T2* 检测到肿瘤Fe增加的受试者 松弛，具有显著增加的无进展生存期（11.2个月对5.7个月）。这表明 T2* 弛豫可能是一种非侵入性的生物标志物，预测铁依赖性反应PAscH-。 Ferumoxotyol（FMX）是一种用于神经胶质瘤MR成像的氧化铁纳米颗粒。初步临床前数据 显示抗坏血酸盐和电离辐射促进Fe从FMX中释放，这可以通过 MRI参数改变（T1增强和T2* 弛豫时间缩短）。释放的Fe将 则可用于治疗增强PAscH-。在GBM人类肿瘤中，FMX介导的T1 增强检测在肿瘤和周围水肿体积中输注后长达72小时的Fe释放。 鉴于这一令人兴奋的初步数据，FMX可能代表理想的GBM成像和治疗剂， 与PASCH-结合。我们假设FMX与PAscH联合补铁， 标准护理疗法将是安全的，并增加氧化还原活性铁含量（通过T2* 弛豫检测） 作为一期临床试验的一部分。将通过T2* MRI分析每例受试者的GBM肿瘤， 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Fe操纵对GBM治疗的影响。如果 成功的，未来的2期研究将调查PAscH和FMX与标准药物联合的潜力。 GBM治疗可提高生存率并使可能对PAscH无反应的受试者敏感-放射性- 化疗

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.