Nature：毒蘑菇不“毒”，帮助抗癌

作者：杨超月

Nature：毒蘑菇不“毒”，帮助抗癌

2015年4月27日讯 /生物谷BIOON/ --有时候癌症研究者们会考虑将来自“死亡之帽”毒蘑菇衍生的毒性α-鹅膏蕈碱作为一种潜在的癌症疗法药物，然而由于α-鹅膏蕈碱会存在引发肝脏毒性的可能，因此其作为有效的疗法往往被认为存在很多限制。

近日一篇刊登在国际杂志Nature上的研究论文中，来自得克萨斯大学MD癌症研究中心的研究人员着眼于开发一种以α-鹅膏蕈碱为基础的抗体共轭药物（ADCs），他们发现ADCs可以以POLR2A基因为靶点来来有效治疗患结直肠癌的小鼠模型，这种药物会有效促进肿瘤消退以及大幅降低自身的毒性，同时ADCs还会改善对癌细胞的靶向作用，尽可能地减少对健康细胞的影响。

Xiongbin Lu教授表示，当传统的肿瘤抑制基因TP53被剔除后就会引发癌症发展，而其附近的基因POLR2A同时也会被剔除；正常细胞中拥有两个拷贝的POLR2A和TP53基因，而本文研究中研究者对含有单一拷贝两个基因的癌细胞进行研究，单一拷贝的两个基因在53%的结直肠癌、62%的乳腺癌以及75%的卵巢癌中存在。

POLR2A是一种包括癌细胞在内的细胞生存的必须基因，由于其仅存在单一拷贝，因此癌细胞对于该基因的抑制会异常敏感。随着POLR2A和TP53基因同时被剔除就意味着靶向作用这两个基因遗传过程的疗法变得不再那么有效，从而使得癌细胞继续旺盛成长；而揭示单一拷贝的POLR2A基因或许就可以促进癌症发展，帮助科学家们寻找新型靶点来进行癌症治疗；文章中研究者检测了ADCs的作用，发现其可以有效抑制POLR2A基因的表达，进而抑制癌症的发展。

在癌症疗法中研究者们花费了很大努力来试图恢复TP53的活性，然而由于TP53信号的复杂性，目前并没有基于TP53的疗法成功转化进入临床的癌症疗法阶段。POLR2A基因可以编码一种酶类，该酶类会被α-鹅膏蕈碱所以只，研究者发现，低剂量α-鹅膏蕈碱引发的基因POLR2A的抑制会阻断癌细胞的生长，并且降低毒性。

最后研究者Lu说道，我们预测，抑制基因POLR2A的表达或许可以作为一种新型的治疗手段来治疗携带常见基因突变的人类癌症。（生物谷Bioon.com）

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Nature：毒蘑菇不“毒”，帮助抗癌

doi:10.1038/nature14418
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TP53 loss creates therapeutic vulnerability in colorectal cancer

Yunhua Liu, Xinna Zhang, Cecil Han, Guohui Wan, Xingxu Huang, Cristina Ivan, Dahai Jiang, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Pulivarthi H. Rao, Dipen M. Maru, Andreas Pahl, Xiaoming He, Anil K. Sood, Lee M. Ellis, Jan Anderl & Xiongbin Lu

TP53, a well-known tumour suppressor gene that encodes p53, is frequently inactivated by mutation or deletion in most human tumours1, 2. A tremendous effort has been made to restore p53 activity in cancer therapies3, 4, 5, 6, 7. However, no effective p53-based therapy has been successfully translated into clinical cancer treatment owing to the complexity of p53 signalling. Here we demonstrate that genomic deletion of TP53 frequently encompasses essential neighbouring genes, rendering cancer cells with hemizygous TP53 deletion vulnerable to further suppression of such genes. POLR2A is identified as such a gene that is almost always co-deleted with TP53 in human cancers. It encodes the largest and catalytic subunit of the RNA polymerase II complex, which is specifically inhibited by α-amanitin8, 9. Our analysis of The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) databases reveals that POLR2A expression levels are tightly correlated with its gene copy numbers in human colorectal cancer. Suppression of POLR2A with α-amanitin or small interfering RNAs selectively inhibits the proliferation, survival and tumorigenic potential of colorectal cancer cells with hemizygous TP53 loss in a p53-independent manner. Previous clinical applications of α-amanitin have been limited owing to its liver toxicity10. However, we found that α-amanitin-based antibody–drug conjugates are highly effective therapeutic agents with reduced toxicity11. Here we show that low doses of α-amanitin-conjugated anti-epithelial cell adhesion molecule (EpCAM) antibody lead to complete tumour regression in mouse models of human colorectal cancer with hemizygous deletion of POLR2A. We anticipate that inhibiting POLR2A will be a new therapeutic approach for human cancers containing such common genomic alterations.