Eribulin penetrates brain tumor tissue and prolongs survival of mice harboring intracerebral glioblastoma xenografts

Glioblastoma is one of the most devastating human malignancies for which a novel efficient treatment is urgently required. This pre-clinical study shows that eribulin, a specific inhibitor of telomerase reverse transcriptase (TERT)-RNA-dependent RNA polymerase, is an effective anticancer agent against glioblastoma. Eribulin inhibited the growth of 4 TERT promoter mutation-harboring glioblastoma cell lines in vitro at subnanomolar concentrations. In addition, it suppressed the growth of glioblastoma cells transplanted subcutaneously or intracerebrally into mice, and significantly prolonged the survival of mice harboring brain tumors at a clinically equivalent dose. A pharmacokinetics study showed that eribulin quickly penetrated brain tumors and remained at a high concentration even when it was washed away from plasma, kidney or liver 24 hours after intravenous injection. Moreover, a matrix-assisted laser desorption/ionization mass spectrometry imaging analysis revealed that intraperitoneally injected eribulin penetrated the brain tumor and was distributed evenly within the tumor mass at 1 hour after the injection whereas only very low levels of eribulin were detected in surrounding normal brain. Eribulin is an FDA-approved drug for refractory breast cancer and can be safely repositioned for treatment of glioblastoma patients. Thus, our results suggest that eribulin may serve as a novel therapeutic option for glioblastoma. Based on these data, an investigator-initiated registration-directed clinical trial to evaluate the safety and efficacy of eribulin in patients with recurrent GBM (UMIN000030359) has been initiated.

胶质母细胞瘤是最具毁灭性的人类恶性肿瘤之一，迫切需要一种新的有效治疗方法。这项临床前研究表明，艾日布林，一种端粒酶逆转录酶（TERT）-RNA依赖的RNA聚合酶的特异性抑制剂，是一种针对胶质母细胞瘤的有效抗癌药物。艾日布林在体外以亚纳摩尔浓度抑制4种携带TERT启动子突变的胶质母细胞瘤细胞系的生长。此外，它抑制了皮下或脑内移植到小鼠体内的胶质母细胞瘤细胞的生长，并在临床等效剂量下显著延长了患脑肿瘤小鼠的生存期。一项药代动力学研究表明，艾日布林能快速穿透脑肿瘤，并且即使在静脉注射24小时后从血浆、肾脏或肝脏中被清除，仍能保持高浓度。此外，基质辅助激光解吸/电离质谱成像分析显示，腹腔注射的艾日布林在注射后1小时穿透脑肿瘤并在肿瘤块内均匀分布，而在周围正常脑组织中仅检测到极低水平的艾日布林。艾日布林是一种经美国食品药品监督管理局批准用于治疗难治性乳腺癌的药物，可以安全地重新定位用于治疗胶质母细胞瘤患者。因此，我们的研究结果表明，艾日布林可能作为胶质母细胞瘤的一种新的治疗选择。基于这些数据，一项由研究者发起的注册导向临床试验（UMIN000030359）已经启动，以评估艾日布林在复发性胶质母细胞瘤患者中的安全性和有效性。