Eribulin penetrates brain tumor tissue and prolongs survival of mice harboring intracerebral glioblastoma xenografts
Eribulin penetrates brain tumor tissue and prolongs survival of mice harboring intracerebral glioblastoma xenografts
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DOI：
10.1111/cas.14067
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发表时间：
2019-07-01
期刊：
影响因子：
5.7
通讯作者：
Ichimura, Koichi
中科院分区：
文献类型：
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作者：
Takahashi, Masamichi;Miki, Shunichiro;Ichimura, Koichi
胶质母细胞瘤是人类最具破坏性的恶性肿瘤之一，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，端粒酶逆转录酶（TERT）-RNA依赖的RNA聚合酶的特异性抑制剂，是一种有效的抗胶质母细胞瘤的抗癌药物。艾日布林在亚纳摩尔浓度下体外抑制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携带脑肿瘤的小鼠的存活时间。一项药代动力学研究表明，艾日布林迅速渗透脑肿瘤，即使在静脉注射后24小时从血浆、肾脏或肝脏中洗去，仍保持高浓度。此外，基质辅助激光解吸/电离质谱成像分析显示，腹腔内注射的艾日布林穿透脑肿瘤，并在注射后1小时均匀分布在肿瘤块内，而在周围正常脑中仅检测到非常低水平的艾日布林。艾日布林是FDA批准的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，艾日布林可能作为一种新的治疗选择胶质母细胞瘤。基于这些数据，研究者发起了一项注册指导临床试验，以评估艾日布林在复发性GBM患者中的安全性和疗效（UMIN 000030359）。
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.