Oncology and genetics
Grabbing cancer by the short and curlies
A new technique for analysing tumours promises better understanding and more effective treatment
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.
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.
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.
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.
On the pin money
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.
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.
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.
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.
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.