Initial testing (stage 1) of tazemetostat (EPZ-6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program.
Initial testing (stage 1) of tazemetostat (EPZ-6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program.
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DOI：
10.1002/pbc.26218
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发表时间：
2017-03
影响因子：
3.2
通讯作者：
Smith MA
中科院分区：
文献类型：
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作者：
Kurmasheva RT;Sammons M;Favours E;Wu J;Kurmashev D;Cosmopoulos K;Keilhack H;Klaus CR;Houghton PJ;Smith MA
他莫司坦(EPZ-6438)是组蛋白甲基转移酶EZH2的选择性抑制剂，目前正在为非霍奇金淋巴瘤和基因定义的肿瘤进行临床开发。他莫司坦对PPTP实体瘤移植瘤进行了试验，剂量为400 mg/kg，每天两次，经口灌胃，共28天。测定对照组和治疗组的H3K27me3：H3比值。在所研究的30例异种移植物中，有9例(30%)的无事件存活率(EFS)分布与对照组相比有显著差异。在7个横纹肌样肿瘤异种移植株中有5个(71%)与23个非横纹肌样肿瘤移植瘤系中的4个(17%)EFS分布有显著差异[卡方(χ2)检验p=0.006]。他莫司坦诱导的肿瘤生长抑制符合中和高EFS治疗控制(T/C)活性的标准，分别为2/25(8%)和1/25(4%)的异种移植瘤。EFST/C测量的中高活性仅在横纹肌样肿瘤移植瘤中观察到(5个横纹肌样肿瘤中3个，而22个非横纹肌样肿瘤中0个(χ2检验p<；0.001)。1例横纹肌样瘤移植瘤(G401)病情稳定。对于1例横纹肌样瘤(G401)，在肿瘤生长1周后观察到肿瘤延迟消退至他西莫司汀。与对照组相比，他西莫司在大多数肿瘤中诱导H3K27me3水平显著降低。他莫司坦在横纹肌样肿瘤模型中显示出显著的抗肿瘤活性，但对任何其他组织学没有表现出一致的活性。他莫司坦降低了H3K27me3水平，与肿瘤反应无关。有必要进行进一步的临床前试验，以评估他赛托斯特与其他抗癌药物的联合作用。
Tazemetostat (EPZ-6438) is a selective inhibitor of the histone methyltransferase EZH2, currently in clinical development for non-Hodgkin lymphoma and genetically defined tumors. Tazemetostat was tested against the PPTP solid tumor xenografts using a dose of 400 mg/kg administered twice-daily by oral gavage for 28 days. H3K27me3:H3 ratios were determined in control and treated tumors. Tazemetostat induced significant differences in event free survival (EFS) distribution compared to control in 9 of 30 (30%) of the xenografts studied. Significant differences in EFS distribution were observed in 5 of 7 (71%) rhabdoid tumor xenograft lines compared to 4 of 23 (17%) non-rhabdoid xenograft lines [chi square (χ2) test p=0.006]. Tazemetostat induced tumor growth inhibition meeting criteria for intermediate and high EFS treated to control (T/C) activity in 2 of 25 (8%) and 1 of 25 (4%) xenografts, respectively. Intermediate and high activity for the EFS T/C metric was observed exclusively among rhabdoid tumor xenografts (3 of 5 rhabdoid tumor versus 0 of 22 non-rhabdoid tumors (χ2 test p<0.001). One rhabdoid tumor xenograft (G401) showed stable disease. For one rhabdoid tumor (G401), delayed tumor regression to tazemetostat was noted following 1 week of tumor growth. Tazemetostat induced significant reduction of H3K27me3 levels in the majority of tumors compared to controls. Tazemetostat demonstrated significant antitumor activity in rhabdoid tumor models, but showed no consistent activity against any other histology. Tazemetostat reduced H3K27me3 levels irrespective of tumor response. Further preclinical testing to evaluate tazemetostat in combination with other anticancer agents is warranted.
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