体内评价赖氨酸特异性去甲基酶（KDM1A/LSD1）抑制剂 SP-2577（塞克西达美司他）针对儿科肉瘤临床前模型的疗效：来自儿科临床前测试联盟（PPTC）的报告。

In vivo evaluation of the lysine-specific demethylase (KDM1A/LSD1) inhibitor SP-2577 (Seclidemstat) against pediatric sarcoma preclinical models: A report from the Pediatric Preclinical Testing Consortium (PPTC).

机构信息

Greehey Children's Cancer Research Institute, San Antonio, Texas, USA.

RTI International, Research Triangle Park, North Carolina, USA.

出版信息

Pediatr Blood Cancer. 2021 Nov;68(11):e29304. doi: 10.1002/pbc.29304. Epub 2021 Aug 28.

DOI:10.1002/pbc.29304

PMID:34453478

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10338045/

Abstract

SP-2577(Seclidemstat), an inhibitor of lysine-specific demthylase KDM1A (LSD1) that is overexpressed in pediatric sarcomas, was evaluated against pediatric sarcoma xenografts. SP-2577 (100 mg/kg/day × 28 days) statistically significantly (p < .05) inhibited growth of three of eight Ewing sarcoma (EwS), four of five rhabdomyosarcoma (RMS), and four of six osteosarcoma (OS) xenografts. The increase in EFS T/C was modest (<1.5) for all models except RMS Rh10 (EFS T/C = 2.8). There were no tumor regressions or consistent changes in dimethyl histone H3(K4), HOXM1, DAX1, c-MYC and N-MYC, or tumor histology/differentiation. SP-2577 has limited activity against these pediatric sarcoma models at the dose and schedule evaluated.

摘要

SP-2577（塞克西得美司他）是一种组蛋白赖氨酸特异性去甲基化酶 KDM1A（LSD1）抑制剂，在儿科肉瘤中过表达，针对儿科肉瘤异种移植进行了评估。SP-2577（100mg/kg/天×28 天）在统计学上显著（p<0.05）抑制了 8 种尤文肉瘤（EwS）中的 3 种、5 种横纹肌肉瘤（RMS）中的 4 种和 6 种骨肉瘤（OS）异种移植的生长。除 RMS Rh10（EFS T/C=2.8）外，所有模型的 EFS T/C 增加均适中（<1.5）。没有肿瘤消退或组蛋白 H3（K4）二甲基化、HOXM1、DAX1、c-MYC 和 N-MYC 的一致变化，或肿瘤组织学/分化。在评估的剂量和方案下，SP-2577 对这些儿科肉瘤模型的活性有限。