Children's Brain Tumour Research Centre, School of Medicine, University of Nottingham, Nottingham, UK.
Royal Manchester Children's Hospital, Children's Brain Tumour Research Network & Institute of Cancer Sciences, The University of Manchester, Manchester, UK.
Sci Rep. 2019 Jul 16;9(1):10290. doi: 10.1038/s41598-019-46700-z.
Three of the hallmarks of poor prognosis in paediatric ependymoma are drug resistance, local invasion and recurrence. We hypothesised that these hallmarks were due to the presence of a sub-population of cancer stem cells expressing the multi-drug efflux transporter ABCB1. ABCB1 gene expression was observed in 4 out of 5 paediatric ependymoma cell lines and increased in stem cell enriched neurospheres. Functional inhibition of ABCB1 using vardenafil or verapamil significantly (p ≤ 0.05-0.001) potentiated the response to three chemotherapeutic drugs (vincristine, etoposide and methotrexate). Both inhibitors were also able to significantly reduce migration (p ≤ 0.001) and invasion (p ≤ 0.001). We demonstrate that ABCB1 positive patients from an infant chemotherapy-led trial (CNS9204) had a shorter mean event free survival (EFS) (2.7 versus 8.6 years; p = 0.007 log-rank analysis) and overall survival (OS) (5.4 versus 12 years; p = 0.009 log-rank analysis). ABCB1 positivity also correlated with reduced event free survival in patients with incompletely resected tumours who received chemotherapy across CNS9204 and CNS9904 (a radiotherapy-led SIOP 1999-04 trial cohort; p = 0.03). ABCB1 is a predictive marker of chemotherapy response in ependymoma patients and vardenafil, currently used to treat paediatric pulmonary hypertension in children, could be repurposed to reduce chemoresistance, migration and invasion in paediatric ependymoma patients at non-toxic concentrations.
预后不良的三个特征在儿童室管膜瘤中是耐药性、局部侵袭和复发。我们假设这些特征是由于存在表达多药外排转运蛋白 ABCB1 的癌症干细胞亚群。在 5 个儿科室管膜瘤细胞系中的 4 个观察到 ABCB1 基因表达，并在富含干细胞的神经球中增加。使用伐地那非或维拉帕米对 ABCB1 的功能抑制显著（p≤0.05-0.001）增强了对三种化疗药物（长春新碱、依托泊苷和甲氨蝶呤）的反应。两种抑制剂也能够显著减少迁移（p≤0.001）和侵袭（p≤0.001）。我们证明，来自婴儿化疗主导试验（CNS9204）的 ABCB1 阳性患者的无事件生存（EFS）（2.7 与 8.6 年；p=0.007 对数秩分析）和总生存（OS）（5.4 与 12 年；p=0.009 对数秩分析）更短。在接受 CNS9204 和 CNS9904 化疗的不完全切除肿瘤患者中，ABCB1 阳性也与无事件生存减少相关（放疗主导的 SIOP 1999-04 试验队列；p=0.03）。ABCB1 是儿童室管膜瘤患者化疗反应的预测标志物，伐地那非目前用于治疗儿科肺动脉高压，可在非毒性浓度下重新用于降低儿童室管膜瘤患者的化疗耐药性、迁移和侵袭。
