肿瘤遗传学

　　Grabbing cancer by the short and curlies

　　短发卡——钳住癌症的新武器

　　A new technique for analysing tumours promises better understanding and more effective treatment

　　一项研究肿瘤的新技术为人类更加深入地了解肿瘤并找到更加有效的治疗方法带来了希望

　　Sep 24th 2011 | SAN FRANCISCO | from the print edition

　　ONE of the great hopes nurtured by the Human Genome Project was that it would crack cancer open. Knowing which genes were going wrong would, the theory went, allow specifically tailored drugs to be developed. And this is, indeed, happening. Only last month America’s Food and Drug Administration approved a medicine called Xalkori (generically, crizotinib) for patients who have a particular type of non-small-cell lung cancer, the most common form of that disease. Xalkori blocks the growth of tumours caused by a mutant form of the gene which encodes a signalling molecule known as anaplastic lymphoma kinase. This mutation occurs in 3-5% of lung-cancer patients, and in trials Xalkori caused a dramatic shrinkage of the tumour in around half of those treated.

　　找到克服癌症的方法，是人类基因组计划带给人们最大的希望之一。理论上，只要找到出错的基因，就能研发出针对它的特定药物。事实上，这些期望正在被逐步实现。就在上个月美国食品药品管理局批准了一种名为Xalkori（通用名：克里唑蒂尼）的新药上市，用于治疗非小细胞肺癌（最常见的一种肺癌）。Xalkori能够抑制由编码信号分子间变性淋巴瘤激酶基因的突变体所导致的癌细胞的增长。3-5%的肺癌患者体内存在这种突变。临床试验中，大约一半受试者在服过此药后体内癌细胞数量显著减少。

　　The catch is that the respite does not last. Typically, someone will respond for about a year, but after that his tumour starts growing again and the disease continues on its course. This is a pattern seen again and again with the new generation of drugs that genomics has helped to create. They slow the disease, but only for a few months. The presumption is that further mutations are arising in a tumour all the time, and that eventually one of them makes a molecular change that nullifies the effect of the drug. Researchers would dearly like to find a way to deal with this.

　　但问题是Xalkori对病情的缓解作用持续时间不长。一般来说，持续服药一年后患者将产生抗药性，体内癌细胞恢复增长导致病情恶化。这是一代代利用基因组学开发出的药物共同的治疗效果变化模式，最终都只能短暂地缓解病情。其机制可能是，癌细胞会不断地产生新的突变体，最终其中的某个突变体编码产生了使药物作用失效的蛋白分子。研究人员正致力于找出对付这种机制的办法。

　　One who is trying to do so is René Bernards of the Netherlands Cancer Institute. On September 18th he told a meeting of the American Association for Cancer Research, held in San Francisco, about a way that the sensitivity of tumour cells to Xalkori might be restored. More important than that, though, is the way he discovered the solution—for this could be applied to many other cases in which an anti-cancer drug is having its useful life curtailed by the development of resistance.

　　来自荷兰癌症研究所的勒内.伯纳兹博士便是其中一位。9月18日，他在旧金山一个由美国癌症研究协会组织的研讨会上宣布，发现了使癌细胞恢复对Xalkori敏感性的方法。然而比这更具意义的是，此种方法的原理，同样适用于打破其他多种由于产生抗药性而导致其疗效减退的抗癌药物所遭遇的瓶颈。

　　One of the problems with cancer is that the mutations which cause it are often hidden in a plethora of others that have no direct bearing on the disease. Normal DNA sequencing cannot distinguish which mutations are important and which are not. Dr Bernards, however, thinks he can, by using molecules called short hairpin RNAs.

　　攻克癌症的困难之一，是致癌突变通常都隐藏在其他众多非致癌突变之中，而正规的DNA测序不能检测区别出两者的不同。不过现在，伯纳兹博士称，利用一种叫做短发夹RNA的分子，他找到了区别二者的方法。

　　On the pin money

　　深入探究

　　RNA is a molecule similar to DNA, except that its molecules are usually much smaller. One of its jobs is to act as a messenger carrying genetic information from a cell’s nucleus to the machinery which makes proteins. Each messenger is an edited copy of one strand of the DNA double helix. Double-stranded RNA does exist, but mostly in viruses. Mammalian cells make only the single-stranded variety. If a cell’s defence mechanisms detect double-stranded RNA they destroy it, to protect against infection.

　　RNA是一种类似于DNA的分子，但是其分子量比DNA小得多。它的职能之一是充当信使将遗传信息从细胞核运送至制造蛋白质的机器——核糖体。每一个信使RNA都是由双螺旋DNA的一个单链编码转录而成。双链RNA通常只存在于病毒体内。哺乳动物细胞只能正常识别单链RNA，如果发现双链RNA就会迅速将其销毁，以保护机体免受病毒感染。

　　This aversity to double-stranded RNA means short hairpins can be used to knock out the messengers, thus nullifying the signal from the underlying gene. It is just a question of making a hairpin with an appropriate genetic sequence—one that is the same as the missing strand of the original DNA—so that the hairpin will combine eagerly with the messenger to form a double-stranded molecule. Modern gene-synthesis techniques mean this is not hard to do. Dr Bernards therefore did it with the messengers of 20,000 genes, to see which, if any, are implicated in the development of resistance to Xalkori.

　　机体对双链RNA的排斥性意味着可以利用短发卡RNA破坏信使RNA，从而阻断相应基因的信号传递。问题的关键是设计出合适的发卡结构，其遗传序列必须与其替代的DNA序列一致，才能迅速准确地结合其编码的RNA成为双链RNA分子。利用DNA合成技术很容易完成这项任务。因此，伯纳兹博士对2000个基因的信使RNA进行一一实验，以确认与产生Xalkori抗药性有关的基因是否存在其中、是具体的哪一个。

　　In fact, he found three. Mediator-12 (MED 12), which helps to transcribe genes from DNA into RNA messengers, was one. The other two were genes that help maintain the structure of chromosomes. Presumably, resistance to Xalkori is being caused by disabling mutations in one or more of these genes.

　　实际上，伯纳兹博士最后确认了三个。一个是Mediator-12(MED 12)，即控制基因转录成信使RNA的中介体复合物亚基12基因，其他两个是帮助维护持染色体结构的基因。可以推断，针对Xalkori的抗药性是由于这三个基因中的一个或多个发生了突变导致的结果。

　　That is interesting, but not of immediate assistance to the dying. What Dr Bernards and his colleagues did next, though, could be of such help. They looked for hairpin RNAs that restored sensitivity to Xalkori in cells whose MED12 messengers were being blocked—and they found one. Disabling the messengers of the gene that encodes a receptor protein called TGF beta-R2, which is found on cell surfaces, caused cells that had once been resistant to Xalkori to shrivel in its presence. Moreover, treating these same Xalkori-resistant cells with an experimental drug designed to block TGF beta-receptors restored sensitivity to Xalkori, though it had no effect on cancer-cell growth on its own.

　　这个发现十分有趣，但是对治疗患者没有直接帮助。伯纳兹博士与同事们接下来所做的工作正符合这个目的。他们尝试寻找能够拦截MED12基因的信使RNA从而恢复细胞对Xalkori敏感性的发夹结构，并取得了成功。TGF beta-R2是一种存在于细胞表面的蛋白质受体，只要破坏编码这种受体DNA的信使RNA，就能消除细胞对Xalkori的抗药性。此外，设计药物针对同样的抗药细胞，使其表面的TGF beta受体被药物屏蔽，也会得到相同的实验结果，即使这种药物本身并没有阻止癌细胞增长的疗效。

　　Dr Bernards thinks that in MED12 he has discovered a pathway crucial for the development of drug resistance. Subsequent studies by members of his group have found that interfering with MED12 messengers causes resistance to numerous other drugs. These include Iressa and Tarceva, which are prescribed for lung cancer; Zelboraf, which is effective against melanoma; and Nexavar, which is used for kidney and liver cancers. If these lab-based results are confirmed in people then TGF beta-receptor inhibitors may prove a way of extending the useful lives of a plethora of medicines.

　　伯纳兹博士认为，通过MED12基因他找出了一个对于细胞产生抗药性十分关键的路径。伯纳兹博士的研究组同事在随后的研究中发现，干扰MED12基因的信使RNA会导致产生对多种药物的抗药性，包括用于治疗肺癌的药物易瑞沙（Iressa）和特罗凯（Tarceva）、黑色素瘤药物左博拉（Zelboraf）以及肾癌和肝癌药物多吉美（Nexavar）。如果这项实验结果在人体内也得到证实，TGF beta受体抑制剂将被用来延长多种药物的使用寿命。

　　Dr Bernards’s work, indeed, is just the vanguard. At least three other groups of researchers are using short hairpin RNA to study cancer in this way, and one of them, led by William Hahn of the Dana-Farber Cancer Institute in Boston, has already found what may be an important molecular link in the development of ovarian tumours. Turning these sorts of laboratory discoveries into treatments is a long and tedious process that often fails. What is crucial about Dr Bernards’s work, though, is that short hairpin RNAs do exactly what the genome project promised: they crack the problem open.

　　伯纳兹博士的研究工作只是这个领域的先头部队，同期至少还有其他三组人也在利用短发卡RNA朝相同方向进行肿瘤研究。其中，由威廉姆.哈恩带领的波斯顿法波癌症研究院研究小组，已经发现可能对卵巢癌发生过程十分重要的分子链。将实验室发现的成果运用到实际治疗中是一个冗长而乏味的过程，其中伴随着无数次失败。而伯纳兹博士的研究工作的决定性意义是，短发卡RNA正像人类基因组计划承诺的那样，找到了问题的突破点。