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增强抗VEGF疗法的BARD1表观遗传调节

Emine Bayraktar¹, Cristian Rodriguez-Aguayo², Elaine Stur³

¹Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Houston, Houston, TX 77030, USA.

Cell reports. Medicine

|September 4, 2025

概括

科学家发现恢复BARD1蛋白水平可以克服抗VEGF治疗的癌症. 这涉及到表观遗传修饰, 提供了一种提高癌症治疗效率的新策略.

科学领域:

癌症学
分子生物学
表观遗传学
抗癌治疗方法

背景情况:

抗血管内皮生长因子抗体 (AVA) 在临床上使用,但经常面临治疗阻力.
不完全了解AVA耐药性的机制,从而阻碍治疗效果.
在这种情况下,BRCA1相关的RING域1 (BARD1) 功能尚未被探索.

研究的目的:

研究BARD1对抗血管内皮生长因子抗体 (AVA) 的调节作用.
探索克服AVA耐药性的表观遗传策略.
开发针对BARD1的新型治疗方法,以加强癌症治疗.

主要方法:

使用DNA甲基化 (全球和向) 的表观遗传调节,以评估BARD1在血管生成中的作用.
用阿扎西丁进行顺序治疗以克服AVA耐药性的体内评估.
为精确表观遗传重新激活,开发一个体CRISPR失活的Cas9 (dCas9) - TET1系统与BARD1向的sgRNAs.

主要成果:

BARD1被确定为血管生成的关键调节剂,影响AVA敏感性.
在体内,阿扎西治疗有效克服了AVA耐药性.
该dCas9-TET1系统成功实现了BARD1促进体的CpG特异性去甲基化,恢复了其表达并改善了AVA反应.
在卵巢癌模型中,通过dCas9- TET1或siRNA恢复BARD1显著降低了结合AVA的瘤生长.

结论:

在瘤血管生成和AVA敏感性方面,BARD1扮演着至关重要的,以前未被认可的角色.
基因特异性表观遗传向,以dCas9-TET1系统为例,为克服AVA耐药性提供了一个有希望的策略.
恢复BARD1表达是一种潜在的治疗途径,可以增强抗血管性癌症疗法.

关键词:

在 AVA 阻力在BARD1 抗VEGF抗体治疗贝瓦西祖马布表观遗传编辑表观遗传疗法卵巢癌其他

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