结合EZH2和ATM抑制在BAP1缺乏性美索瘤中
Nick Landman1,2, Danielle Hulsman1,2, Jitendra Badhai1,2
1Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, The Netherlands.
British journal of cancer
|March 23, 2024
概括
将EZH2抑制与ATM抑制结合起来,对治疗BAP1缺陷大脑细胞瘤有很大的希望. 这种组合疗法可以改善BAP1变异的中瘤患者的疗效并克服抗药性.
科学领域:
- 在瘤学瘤学.
- 癌症遗传学 癌症遗传学
- 药物发现 药物发现 药物发现
背景情况:
- 超过50%的间皮瘤瘤在BAP1瘤抑制基因中表现出改变.
- 缺少BAP1的间皮瘤对EZH2抑制具有临床前的敏感性,但临床疗效不大.
- 组合疗法可以增强EZH2抑制效果,并防止获得的耐药性.
研究的目的:
- 为了确定针对BAP1缺乏性半径瘤的新型组合疗法.
- 评估EZH2抑制与其他抗癌剂结合的协同潜力.
主要方法:
- 20种化合物与EZH2抑制相结合的药物协同作用屏幕在间皮瘤细胞系中进行.
- 使用Bliss模型评估了协同效应的潜力.
- 在体内异种移植实验中验证了这些发现.
主要成果:
- 将EZH2抑制与ATM抑制 (ATMi) 结合起来,证明了对抗BAP1缺陷半质瘤的协同潜力.
- 这种组合在临床前模型中显著增强了瘤生长抑制.
- 在BAP1耗尽后观察到较低的ATM水平,可能由E2F1.1调解.
结论:
- 在临床前的模型中,ATM和EZH2抑制的组合对BAP1缺陷半质瘤有效.
- 这种组合代表了一种潜在的新型治疗策略,用于中皮瘤.
- BAP1可以作为这种向治疗的预测生物标志物.
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