Convection-Enhanced Delivery of Enhancer of Zeste Homolog-2 (EZH2) Inhibitor for the Treatment of Diffuse Intrinsic Pontine Glioma.
Convection-Enhanced Delivery of Enhancer of Zeste Homolog-2 (EZH2) Inhibitor for the Treatment of Diffuse Intrinsic Pontine Glioma.
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DOI：
10.1093/neuros/nyaa301
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发表时间：
2020-07
期刊：
影响因子：
4.8
通讯作者：
Takahiro Sasaki;H. Katagi;S. Goldman;O. Becher;R. Hashizume
中科院分区：
文献类型：
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作者：
Takahiro Sasaki;H. Katagi;S. Goldman;O. Becher;R. Hashizume
背景弥漫性桥脑胶质瘤(DIPG)是一种致命的儿童脑肿瘤，大多数患者在初诊后2年内死亡。导致这些患者预后不佳的因素包括脑的浸润性和解剖位置，这排除了手术切除的可能性，以及血脑屏障(BBB)的存在，这减少了全身用药的分布。对流增强给药(CED)是一种直接将治疗药物输送到脑内靶点的输注技术，能够将高浓度的药物输送到输液部位，而不会出现全身毒性。目的评价CED法应用Zust Homolog-2增强子(EZH2)抑制剂对人DIPG异种移植模型的治疗作用。方法采用液-质联用(LC/MS)法检测脑干肿瘤组织中EZH2抑制剂EPZ-6438的浓度。我们用EPZ-6438全身(腹膜)或CED给药治疗荷人DIPG异种移植小鼠。通过生物发光图像监测颅内肿瘤生长情况，并通过动物存活评价治疗效果。结果LC/MS分析表明，全身给药后脑干肿瘤组织中EPZ-6438的浓度为血药浓度的3.74%。与全身注射EPZ-6438相比，EPZ-6438的CED可抑制肿瘤生长并显著延长动物存活时间(P=.0475)。结论EZH2抑制剂的CED是一种有希望的绕过血脑屏障、提高EZH2抑制剂治疗DIPG疗效的策略。
BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brain tumor and the majority of patients die within 2 yr after initial diagnosis. Factors that contribute to the dismal prognosis of these patients include the infiltrative nature and anatomic location in an eloquent area of the brain, which precludes total surgical resection, and the presence of the blood-brain barrier (BBB), which reduces the distribution of systemically administered agents. Convection-enhanced delivery (CED) is a direct infusion technique to deliver therapeutic agents into a target site in the brain and able to deliver a high concentration drug to the infusion site without systemic toxicities. OBJECTIVE To assess the efficacy of enhancer of zeste homolog-2 (EZH2) inhibitor by CED against human DIPG xenograft models. METHODS The concentration of EZH2 inhibitor (EPZ-6438) in the brainstem tumor was evaluated by liquid chromatography-mass spectrometry (LC/MS). We treated mice-bearing human DIPG xenografts with EPZ-6438 using systemic (intraperitoneal) or CED administration. Intracranial tumor growth was monitored by bioluminescence image, and the therapeutic response was evaluated by animal survival. RESULTS LC/MS analysis showed that the concentration of EPZ-6438 in the brainstem tumor was 3.74% of serum concentration after systemic administration. CED of EPZ-6438 suppressed tumor growth and significantly extended animal survival when compared to systemic administration of EPZ-6438 (P = .0475). CONCLUSION Our results indicate that CED of an EZH2 inhibitor is a promising strategy to bypass the BBB and to increase the efficacy of an EZH2 inhibitor for the treatment of DIPG.