让癌细胞“休眠”?Nature首秀:一类奇妙的抗癌新药
2018/08/05
癌细胞很狡猾,善于伪装且分裂、转移能力强。科学家们一直试图针对性地“揪住它们”。近日,科学家们研发出一款新型抗癌药物——可以让癌细胞“永久休眠”。这一作用可以阻止癌症的恶化、复发,且不会像传统的放化疗那样产生难熬的副作用。


Killer T cells surround a cancer cell. Credit: NIH

这一喜人的成果于8月1日发表在《Nature》期刊。来自于墨尔本3所科研机构的科学家们合力开发出首个“让癌细胞休眠”的抗癌药物,可以在不破坏细胞DNA的前提下阻止肿瘤生长和扩散。

这一创新为癌症患者提供了一种令人兴奋的治疗新选择,并且已经在血液癌、肝癌模型中表现出抑制癌症恶化和复发的良好效果。


永久休眠

Walter and Eliza Hall研究所的副教授Tim Thomas、Anne Voss、Monash医药科学研究所的Jonathan Baell教授和来自于Cancers Therapeutics CRC的Brendon Monahan博士合作,试图弄清楚:抑制KAT6A、KAT6B是否有望成为一种新的抗癌疗法?

KAT6A和KAT6B两种蛋白都在驱动癌症发展中发挥着重要作用,特别是KAT6A在“最常见致癌基因”排行榜中位居12名,隶属于赖氨酸乙酰转移酶(KATs)蛋白家族。

“最初,我们在淋巴瘤动物模型中发现,敲除KAT6A基因能够让患癌动物的预期寿命延长3倍!认识到KAT6A是癌症的重要诱因后,我们开始寻找抑制这种蛋白质、治疗癌症的化合物。” Tim Thomas解释道,“在临床前测试中,这类化合物已经展现出巨大的抗癌潜力,我们对其有望成为抗癌新武器感到非常兴奋。”

Tim Thomas表示,这类新药是首个靶向抑制KAT6A和KAT6B蛋白的药物(WM-8014和WM-1119),其作用机制是切断癌细胞“触发”细胞周期以实现无限复制的通路。这一操作并不会让癌细胞死亡,但可以使它们不再能分裂、扩增,从而进入“休眠”状态。

在临床前模型中,这类化合物耐受性良好、对肿瘤细胞非常有效,且对健康细胞没有负面影响。

没有更多的DNA损伤

科研人员在这类新药上投入了近10年的心血,它与标准的癌症疗法之间有一个关键的区别——不造成额外的DNA损伤。

通常,放化疗通过造成不可逆的DNA损伤诱导癌细胞死亡。但是,这些传统疗法并不只是针对癌细胞,也会对健康细胞造成损伤,从而引发令人痛苦的副作用,例如呕吐、疲劳、脱发和感染,甚至于一些长期影响(不孕、其他癌症风险增加)。

Anne Voss表示,“这种新型抗癌药物不会像化疗和放疗那样造成潜在的风险,它只会让癌细胞永久休眠。”

研究团队相信,这一药物可能对阻止癌症复发有效果。“在进入临床试验之前,我们依然有很多工作要做。但是,我们的研究表明,这一药物可以作为巩固疗法,在初次治疗之后使用,用于延缓或者防止癌症复发。” Anne Voss期望着。

责编:悠然

参考资料:

New anti-cancer drugs put cancers to sleep—permanently

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  • Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth

    Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function1. Among the genes coding for the MYST family of KATs (KAT5–KAT8) are the oncogenes KAT6A (also known as MOZ) and KAT6B (also known as MORF and QKF)2,3. KAT6A has essential roles in normal haematopoietic stem cells4,5,6 and is the target of recurrent chromosomal translocations, causing acute myeloid leukaemia7,8. Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers8. KAT6A suppresses cellular senescence through the regulation of suppressors of the CDKN2A locus9,10, a function that requires its KAT activity10. Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days11. These findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer. Here we present highly potent, selective inhibitors of KAT6A and KAT6B, denoted WM-8014 and WM-1119. Biochemical and structural studies demonstrate that these compounds are reversible competitors of acetyl coenzyme A and inhibit MYST-catalysed histone acetylation. WM-8014 and WM-1119 induce cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF-dependent and is accompanied by changes in gene expression that are typical of loss of KAT6A function. WM-8014 potentiates oncogene-induced senescence in vitro and in a zebrafish model of hepatocellular carcinoma. WM-1119, which has increased bioavailability, arrests the progression of lymphoma in mice. We anticipate that this class of inhibitors will help to accelerate the development of therapeutics that target gene transcription regulated by histone acetylation.

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