Cancer answer?

Researchers are working on a more individual approach to each tumour


On the trail of a killer
Photograph by Tsar Fedorsky/Getty ImagesLeif Ellisen says 'smart drugs' will one day change the way cancer is treated


This summer, Vancouver cancer researchers announced a medical first. Presented with an extremely rare case of tongue cancer—it was so unusual there were no standard treatments to use—they sequenced the DNA of the patient’s tumour, and discovered similarities with another cancer (renal cell carcinoma, a type of kidney cancer) for which there’s a known therapy. The patient received drugs tailored to these results, and the cancer stopped growing for several months. Steven Jones, a molecular biologist with the B.C. Cancer Agency Genome Sciences Centre and one of two lead researchers on the study, calls it a breakthrough. It isn’t standard in hospitals to genetically sequence a patient’s tumour, but “the goal would be, maybe in 10 years, this would be routine,” he says.

Dr. Leif Ellisen, an associate professor of medicine at Harvard Medical School, is working to bring tumour genotyping from the lab into the clinic. He and a team have designed a system that can screen relatively large numbers of patients for a variety of mutations across different cancer genes. These genetic mutations are a tumour’s “Achilles’ heel,” noted a recent editorial in the journal EMBO Molecular Medicine. “Every tumour has a flaw,” says Ellisen, who’ll be discussing his work as part of the Scienta Health Series in Toronto on Oct. 7, and his goal is to find it.

It’s the mantra of a growing number of researchers, who tout personalized medicine—treatments tailored to each individual—as the future of cancer care. Traditionally, cancer treatment “has been one-size-fits all,” Ellisen says. “If it’s breast cancer, you treat it one way; if it’s lung cancer, you treat it another.” The downside is that costly drugs are administered to patients, sometimes with harmful side effects and no real promise they’ll work. “The treatment needs to be tailored to the individual characteristics of the patient and, we’re learning now, the characteristics of the tumour,” he says. Cancers are typically classified by the organs where they arise, but it’s possible that a breast cancer and a lung cancer, for example, might share a genetic abnormality. As a result, they might even respond to the same treatment.

That’s the concept behind smart drugs, which are being developed to target specific molecular pathways activated by cancer gene mutations. “These drugs work in a very specific way, as opposed to chemotherapy, which works in a general way,” Ellisen says. One example is Herceptin, a drug that treats certain types of breast cancer. Herceptin inhibits a gene amplified in some women, but not others, that acts like a growth factor for cancer cells. Now, when breast cancer patients are diagnosed, “one of the first tests done on the tumour is to look for this gene,” called HER2, Ellisen says. “If it’s activated, the patient will get Herceptin. If not, they won’t, because it wouldn’t benefit them.”

A broader test might pick up on mutations we wouldn’t expect to see in a given tumour, but which might have a known treatment available. “We needed to develop a technology to look across the spectrum of cancer genes in the tumours,” Ellisen says. “That’s the only way we could personalize the therapy.” The genotyping system they developed can test for over 150 mutations in 18 cancer genes. In a journal, Ellison and his fellow researchers said they opted to scan for “cancer mutations most likely to have immediate clinical impact,” either because they’re already targeted by FDA-approved drugs, or new drugs in development.

Genotyping tumours in the lab is one thing, but in a hospital setting with actual patients, it’s quite different.

“One of the biggest challenges was purifying and analyzing genetic material” in a quick and reproducible fashion, Ellisen says. Tumour samples are generally “set in fixatives, embedded in wax blocks, and stored at room temperature,” he says, and the specimens themselves can have impurities, with tumour cells mixed in with normal ones. All this can, in some cases, make it much harder to detect mutations. Thanks to a series of robots the team designed, the lab can handle complete snapshot genotyping of up to 50 samples a week, “a substantial fraction of all the cancers diagnosed at Mass Gen,” says Ellisen, co-executive director of the hospital’s Cancer Center’s Translational Research Laboratory, which is focused on personalized cancer care.

Ellisen acknowledges we’ve still got a lot to learn. “We don’t know all the cancer genes that exist,” he says, and we need more and better drugs to treat them. (The sequence of the first cancer genome was published just two years ago.) But the field is advancing in leaps and bounds. In April, the International Cancer Genome Consortium, made up of several countries including Canada and the U.S., announced a plan to map the genomes of 25,000 cancer samples. (Canadian researchers are focused on prostate and pancreatic tumours, while the U.S. is working on brain, lung and others.) “There’s been a million-fold improvement in sequencing technology since 2001,” says Dr. Tom Hudson, president and scientific director of the Ontario Institute for Cancer Research. Even so, he expects it will take up to 10 years to complete it.

As we learn more about cancer genes, Ellisen’s system can be updated. “This platform is very scalable, so we can add mutations as new discoveries are made,” he says. Because it’s relatively simple, it could be adopted in clinics elsewhere, he believes. The cost of a test is similar to an MRI scan. Meanwhile, other cancer centres are trying out different genotyping systems, and sharing information about what works best.

The day when cancer patients can be routinely treated based on the genetic makeup of their tumours is still a ways off.

As Ellisen notes, there’s “only a relatively small number of effective targeted therapies available for routine clinical use,” although that number is growing. As we continue to unravel the genetic mutations that lead to cancer, and develop smart drugs to target them, treatment will change drastically, he and others predict.

“There’s no question that this is going to be the way cancer is approached in the future,” Ellisen says.