Nat Med：表观遗传药物GSKJ4或可用于治疗儿童脑癌

2015-01-05 张笑中国科学报

在线发表于《自然—医学》上的一项小鼠研究介绍了几种用于治疗一种致命的侵略性儿童脑癌的选择方案。该研究发现揭示了精确医疗的潜在可能性即将针对病人基因变化的特定药物与病人配对使用，同时也意味着针对该儿童脑癌的研究有了新的治疗进展。这种儿童脑癌名为弥漫性内在脑桥胶质瘤，目前几乎没有什么治疗手段可以治疗这种病，而且由于肿瘤会扩散到大脑各个重要区域，因而手术治疗也不可行。最近的基因研究显示，该癌症的肿瘤通常

在线发表于《自然—医学》上的一项小鼠研究介绍了几种用于治疗一种致命的侵略性儿童脑癌的选择方案。该研究发现揭示了精确医疗的潜在可能性即将针对病人基因变化的特定药物与病人配对使用，同时也意味着针对该儿童脑癌的研究有了新的治疗进展。

这种儿童脑癌名为弥漫性内在脑桥胶质瘤，目前几乎没有什么治疗手段可以治疗这种病，而且由于肿瘤会扩散到大脑各个重要区域，因而手术治疗也不可行。最近的基因研究显示，该癌症的肿瘤通常会在一个组蛋白中频繁产生基因变化——组蛋白是负责将细胞内DNA包装并调节基因表达的一类蛋白。这种特殊的基因变化会阻碍负责修改这些组蛋白的一种调节复合物的活动，从而导致癌症的扩散。

Rintaro Hashizume等人对现有的一种药物GSKJ4进行了测试——该药物与上述被阻断的调节物均作用于同一通路，他们选取了体内组蛋白发生突变的患癌小鼠进行实验，尝试用该药物逆转突变的效果。他们报告称，在用该药物对已确定的肿瘤进行治疗后，小鼠存活率提高了。

此前GSKJ4主要用于白血病的研究，这是此前在白血病中的研究，发表在Nature上。

葛兰素史克(GlaxoSmithKline)制药公司已经在开发一种叫做GSKJ4的实验化合物，GSKJ4的治疗路径遵循了新研究中揭示的这一生物路线图。Aifantis说，如果在进一步的测试中GSKJ4能够发挥作用阻止JMJD3失稳定及逐出PRC2，它有可能为成为几十年来替代标准化疗针对这种形式白血病的第一个治疗方案。

Aifantis说：“揭示出JMJD3的作用，并成功地阻断该酶停止了肿瘤的发展，表明这些针对T细胞急性淋巴细胞白血病的新疗法不仅是理论上的，也是实际可行的。”

Aifantis说，自2012年在《自然医学》(Nature medicine)杂志上首次报道白血病中的这一现象以来，最新的研究发现是他的小组数年来开展研究工作，旨在精确地揭示出PRC2抑制肿瘤生长的机制所达到的一个高潮。在当前的研究中，他们明确地阐明了去甲基化是如何触动一连串事件将PRC2逐出细胞，由此除去PRC2对NOTCH1的抑制，使得NOTCH1能够直接结合并激活致癌基因的。

具体说来，他们将焦点放在了由PRC2控制并甲基化的一个蛋白：histone 3 lysine 27 (H3K27)，以及与H3K27密切相关的两种酶JMJD3及UTX上。

研究发现，在肿瘤生长和发展的所有阶段JMJD3在小鼠和人类白血病细胞中均高度活化。相比之下，在白血病中UTX并没有过量生成，但它在非癌性小鼠和人类细胞中高度活化。当用实验药物GSKJ4处理小鼠和人类白血病细胞时，JMJD3活性终止，所有癌细胞最终死亡。

随后的遗传实验表明，在无法生成JMJD3的培育白血病小鼠中NOTCH1活性下降，而UTX活性仍维持在相同水平。他们发现在没有UTX的培育小鼠中疾病以更快的速度发展，而如果生成UTX，小鼠生存的时间则更长。这些研究结果表明UTX的生成控制了几种肿瘤抑制基因。

为了进一步证实他们的研究发现，研究人员筛查了来自T细胞急性淋巴细胞白血病儿童和成人的200多份血液样本，揭示出了UTX的几种常见突变。

Aifantis表示正在计划测试GSKJ4对抗移植到小鼠体内的人类白血病细胞的疗效。还会利用其他一些实验在白血病动物中联合使用这一药物分子和标准化疗。

原始出处：

Hashizume R1, Andor N2, Ihara Y2, Lerner R2, Gan H3, Chen X3, Fang D3, Huang X4, Tom MW2, Ngo V5, Solomon D6, Mueller S7, Paris PL5, Zhang Z3, Petritsch C2, Gupta N2, Waldman TA8, James CD1.Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma.Nat Med. 2014 Dec;20(12):1394-6. doi: 10.1038/nm.3716. Epub 2014 Nov 17.

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2015-10-11 hlycom3356

感谢作者分享

76 0
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2015-08-06 hlycom3356

期待有更多研究

102 0
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2015-12-19 liye789132251

#Nat#

26 0
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2015-01-07 ms2694732865965676

#脑癌#

23 0
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2015-01-07 ms3994565386320060

#Med#

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