Phage Therapy Group, Division of Brain Sciences, Imperial College London, London, UK.
John Fulcher Neuro-Oncology Laboratory, Division of Brain Sciences, Imperial College London, London, UK.
Cell Death Dis. 2018 Dec 13;9(12):1192. doi: 10.1038/s41419-018-1195-4.
Glioblastoma multiforme (GBM) remains a cancer with a poor prognosis and few effective therapeutic options. Successful medical management of GBM is limited by the restricted access of drugs to the central nervous system (CNS) caused by the blood brain barrier (BBB). We previously showed that a subset of GBM are arginine auxotrophic because of transcriptional silencing of ASS1 and/or ASL and are sensitive to pegylated arginine deiminase (ADI-PEG20). However, it is unknown whether depletion of arginine in peripheral blood in vivo has therapeutic activity against intracranial disease. In the present work, we describe the efficacy of ADI-PEG20 in an intracranial model of human GBM in which tumour growth and regression are assessed in real time by measurement of luciferase activity. Animals bearing intracranial human GBM tumours of varying ASS status were treated with ADI-PEG20 alone or in combination with temozolomide and monitored for tumour growth and regression. Monotherapy ADI-PEG20 significantly reduces the intracranial growth of ASS1 negative GBM and extends survival of mice carrying ASS1 negative GBM without obvious toxicity. The combination of ADI-PEG20 with temozolomide (TMZ) demonstrates enhanced effects in both ASS1 negative and ASS1 positive backgrounds.Our data provide proof of principle for a therapeutic strategy for GBM using peripheral blood arginine depletion that does not require BBB passage of drug and is well tolerated. The ability of ADI-PEG20 to cytoreduce GBM and enhance the effects of temozolomide argues strongly for its early clinical evaluation in the treatment of GBM.
多形性胶质母细胞瘤（GBM）仍然是一种预后不良且治疗选择有限的癌症。由于血脑屏障（BBB）的存在，药物进入中枢神经系统（CNS）的受限，成功治疗 GBM 受到限制。我们之前曾表明，由于 ASS1 和/或 ASL 的转录沉默，一部分 GBM 是精氨酸营养缺陷型的，并且对聚乙二醇化精氨酸脱亚氨酶（ADI-PEG20）敏感。然而，尚不清楚体内外周血中精氨酸的耗竭是否对颅内疾病具有治疗活性。在本工作中，我们描述了 ADI-PEG20 在人 GBM 颅内模型中的疗效，其中通过测量荧光素酶活性实时评估肿瘤生长和消退。用 ADI-PEG20 单独或与替莫唑胺联合治疗具有不同 ASS 状态的颅内人 GBM 肿瘤的动物，并监测肿瘤生长和消退。单独使用 ADI-PEG20 可显著抑制 ASS1 阴性 GBM 的颅内生长，并延长携带 ASS1 阴性 GBM 的小鼠的存活期，而无明显毒性。AD I-PEG20 与替莫唑胺（TMZ）联合使用在 ASS1 阴性和 ASS1 阳性背景下均显示出增强的效果。我们的数据为使用外周血精氨酸耗竭治疗 GBM 的治疗策略提供了原理证明，该策略不需要药物通过 BBB，并且耐受性良好。ADI-PEG20 能够减少 GBM 细胞并增强替莫唑胺的作用，强烈支持其在 GBM 治疗中的早期临床评估。
