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

项目摘要(&A) 胶质母细胞瘤(GBM)是一种致命的原发脑癌，中位总生存期(OS)仅为14-16 月份。尽管治疗方案包括手术切除后再进行放化疗，但 大多数患者会在确诊后7个月内复发。我们在1期试验中确定了药理作用 抗坏血酸(PASCH-；静脉注射维生素C在血浆中达到≈20 mM)结合标准的基底膜疗法是很好的 对于MGMT阳性/IDH1野生型肿瘤预后较差的患者，耐受性良好。这 导致最近完成了PASCH-GBM第二阶段试验(NCT02344355)的登记工作，该试验接受了 标准辐射和替莫唑胺和帕什-。GBM 2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械观测，即帕什选择性地增强了GBM无线电-- 由于氧化还原活性代谢的差异，化疗相对于正常的人类星形胶质细胞 铁(Fe)。这一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(过氧化氢)形成的组织。过氧化氢可以直接对癌细胞产生毒性，或者可以 通过Fenton化学反应产生羟基自由基，破坏DNA、蛋白质和脂类 因此与放化疗有协同作用。此外，对PASCH-GBM相的初步分析 2项试验证实，通过磁共振成像(MRI)T2*检测到的肿瘤Fe升高的受试者 松弛治疗显著增加了无进展生存期(11.2个月比5.7个月)。这表明 T2*松弛可作为预测PASCH-铁依赖反应的非侵入性生物标志物。 阿魏酸(FMX)是一种用于脑胶质瘤磁共振成像的氧化铁纳米颗粒。初步临床前数据 表明抗坏血酸和电离辐射促进了FMX中铁的释放，可以通过 MRI参数的改变(T1增强和T2*弛豫时间缩短)。释放的铁会 然后可用于帕什-的治疗增强。在GBM人肿瘤中，FMX介导的T1 增强扫描检测到注射后长达72小时的铁在肿瘤和周围的水肿区的释放。 考虑到这一令人兴奋的初步数据，FMX在以下情况下可能代表理想的GBM成像和治疗试剂 与Pasch-相结合。我们假设补充铁与FMX和PASCH-和 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*松弛检测) 作为1期临床试验的一部分。每个受试者的基底膜肿瘤将通过T2*MRI进行分析 氧化还原活性铁的变化以及评估血浆中铁超载和肝损伤的证据。 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。如果 成功的、未来的第二阶段研究将调查将PASCH-和FMX与标准相结合的潜力 GBM疗法，以提高存活率，并使原本可能对Pasch-Radio无效的受试者变得敏感- 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.