From unknown cancer gene to potential cancer drug

Not Exactly Rocket ScienceBy Ed YongOct 27, 2011 9:00 PM


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It’s a seemingly simple idea: if you can find the genetic changes that turn normal cells into cancerous ones, you could find new ways of treating cancer. But that’s easier said than done. The genome of a cancer cell is a chaotic mess. Typos build up throughout its DNA, corrupting the encoded information. Entire sections can be flipped, relocated, doubled and deleted. Some of these changes drive the cells to grow and multiply uncontrollably; others are irrelevant passengers that are just along for the ride. Separating the former form the latter is like finding a needle in a haystack made of needles. And that’s exactly what Elisa Oricchio from the Sloan-Kettering Memorial Cancer Center has done. Using powerful genetic techniques, she has identified a gene – EPHA7 – whose loss can lead to a sluggish but hard-to-treat type of lymphoma called follicular lymphoma. The gene encodes a protein of the same name, and Oricchio even used the EPHA7 protein to shrink the size of tumours in mice with lymphoma. Oricchio is still a long way from a drug that could treat human patients, but she has already taken several important steps. Mere months ago, no one knew about EPHA7’s role in lymphoma. Now, the team is already working on developing it into a potential treatment. It’s a stark reminder of the power of modern genetics, and the promise that it heralds for cancer research. Follicular lymphomas tend to grow slowly, and while they’re incurable, they can also be kept under control for years or decades. With the use of new antibodies like rituximab, people could soon expect to survive up to 20 years after a diagnosis. That all sounds rosy, but these cancers are very common and many people suffer multiple relapses. The laid-back tumours also have a habit of transforming into a much more aggressive type that’s hard to treat and spreads rapidly. Oricchio analysed the genomes of 64 follicular lymphomas and found 92 genetic changes that occurred in at least ten percent of them. One such change stood out – a quarter of the tumours were missing a big chunk of their sixth chromosome called 6q. Other studies have found something similar, and some scientists have shown that people who are missing this segment have poorer odds of survival. There must be something in the missing segment that normally keeps cancer at bay, but it’s so large and varied that the identity of the key gene (or genes) isn’t obvious. To narrow things down, Oricchio systematically silenced every single gene within the missing piece of chromosome. She used small RNA molecules designed to take them out of play individually. Again, one candidate stood out – EPHA7. Without it, mice were more likely to develop follicular lymphomas, and they did so more quickly. "We have known for a long time that 6q is deleted in many cases of lymphoma, but until this study, we had little information as to which genes might be implicated,” says Peter Johnson from the University of Southampton, who wasn’t involved in the study. When Oricchio looked at a broader collection of follicular lymphomas, she found that EPHA7 is completely inactivated in around three quarters of them. Whether deleted outright or tagged in way that makes it unreadable, it no longer does its job. EPHA7 is a jack of many trades: it helps to carry chemical signals between cells, it’s active when embryos are developing, and it’s important for the development the nervous system. The gene produces two different proteins – a full-length version that stays on the surface of cells, and a shortened one that can be shed. Oricchio found that white blood cells (the ones that give rise to lymphomas) only produce the shortened version. This abridged protein blocks a network of genes that can fuel the development of lymphoma. EPHA7, it turns out, is a “tumour suppressor”, one of a number of genes that keep cancers in check. So, losing the EPHA7 gene, and the short protein that it produces, increases the risk of lymphoma. But how do you fix the problem? One option would be to go into the cells and add back the missing gene. But there was an alternative. The EPHA7 protein is shed from cells and dissolves in liquid, so it should be possible to compensate for its loss by simply purifying it and injecting it back into tumours. Oricchio did just that, and found that the restored protein can protect against tumours. In mice with human lymphomas, the extra dose of EPHA7 stopped the cancer cells from growing, prompted them to kill themselves, and forced the tumours to shrink. Oricchio even managed to target the protein directly to the tumours, by fusing it to an antibody called rituximab, which homes in on lymphoma cells. The antibody acts as a guidance system that sends an EPHA7 missile to the right target. EPHA7 is also lost in other types of lymphoma and possibly other types of cancer, including prostate, lung, stomach and bowel. Perhaps restoring the missing protein could also help to treat these cancers. There’s still a lot of research to do, though. Next, Oricchio wants to work out which part of the EPHA7 protein keeps lymphoma at bay, for a smaller fragment would be easier to make and deliver. She also wants to compare the protein to current treatments, such as rituximab on its own. As Erika Check Hayden brilliantly argues here, simply sequencing the genes of a cancer isn’t always enough to pinpoint clues that will lead to treatments. However, sequencing might hold more promise when people combine it with other powerful genetic techniques, as Oricchio has done. “This is a great example of how new genetic studies can not only dissect out the genes involved in lymphoma development, but can also point out whole new lines of treatment, using changes in the malignant cells as their Achilles’ heel,” says Johnson. Reference: Oricchio, Nanjangud, Wolfe, Schatz, Konstantinos, Mavrakis, Jiang, Liu, Bruno, Heguy, Olshen, Socci, Teruya-Feldstein, Weis-Garcia, Tam, Shaknovich, Melnick, Himanen, Chaganti & Wendel. 2011. The Eph-Receptor A7 Is a Soluble Tumor Suppressor for Follicular Lymphoma. Cell by Euthman

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