HOUSE_OVERSIGHT_015499.jpg

NAUTIL.US | TEXT SETS

Even if each outlier case only applies to 3 or 7 percent of one type of cancer, as more cases are solved, the benefits quickly add up. “We’re talking about small subsets of patients that together make a radical change,” says Funda Meric-Bernstam, chair of the Department of Investigational Cancer Therapeutics at MD Anderson, who leads the unusual responders program. In some cases, existing cancer drugs can simply be repurposed, such as discovering that an immunosuppressant drug works for certain bladder cancers. Or it might mean finding new life for an experimental drug that had been abandoned. If Conley and Doroshow can pinpoint who might be helped by an abandoned drug, a pharmaceutical company might have to do just one or two further studies to get that drug approved for routine use.

The future might look something like what’s been going on for several years at the Genome Institute of Washington University, where genome sequencing is being used to help people with relapsed cancers and who have run out of options. The project puts insights from studies like Solit’s into practice, analyzing a patient’s tumor to determine whether currently available drugs might target the troublemaker mutations. Combining whole genome sequencing, exome sequencing, and RNA expression analysis—what Washington University professor of genetics and Genome Institute co-director Elaine Mardis calls the “Maserati approach”—the team compares a comprehensive genetic profile against a database of drugs that target specific gene variants, looking for a match.

If there is a match, the results can be impressive, as was the case with a young Washington University doctor with leukemia, Lukas Wartman, who had suffered two relapses. In his case, analysis revealed that a gene called FLT3 was expressing more RNA than normal. A drug that inhibits this gene, usually used in kidney cancer, sent his cancer into remission. Washington University now has a special genetic test for patients with his type of leukemia.

Just recently, Solit’s group solved another exceptional responder mystery—a case of ureteral cancer eliminated with a combination of old and new drugs. The old drug is a standard chemotherapy treatment that prevents DNA from unwinding, which it must do in order to duplicate itself during cell division. The new one sensitizes cells to the effects of radiation. This patient turned out to have a mutation in RAD50, involved in repairing broken DNA strands (badly repaired DNA can lead to uncontrolled cancerous growth). Here, too, the outlier finding may lead to a new treatment, since about 4 percent of the other tumors Solit has looked at have mutations that affect part of the RAD50 complex. “To look at these individuals’ cancers can tell us a lot more than just a random case of cancer,” says Solit. “There’s a phenotype—a response—that gives you information about the genes.”

Solit is now making a quick, reliable test for the TSC1 mutation to single out people with bladder cancer who might be helped by everolimus, and is planning a new study to test the drug in them. And the original outlier, the woman with bladder cancer? Three years later, she’s still on everolimus and still having a “complete response,” Solit says. She’s doing fine.

kat mcgowan is a contributing editor at Discover magazine and an independent journalist based in Berkeley, Calif., and New York City.

39

HOUSE_OVERSIGHT_015499