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Even if each outlier case only applies to 3 or 7 per- cent 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 radi- cal change,” says Funda Meric-Bernstam, chair of the Department of Investigational Cancer Therapeutics at MD Anderson, who leads the unusual responders pro- gram. In some cases, existing cancer drugs can simply be repurposed, such as discover- ing that an immunosuppressant drug works for certain bladder cancers. Or 1t might mean find- ing 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 phar- maceutical company might have to do just one or two fur- ther studies to get that drug approved for routine use.
The future might look some- thing like what’s been gomg on for several years at the Genome Institute of Washington Univer- sity, where genome sequenc- ing 1s being used to help people with relapsed cancers and who have run out of options. The project puts insights from stud- ies 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 pro- fessor 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 suf- fered 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
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kidney cancer, sent his cancer into remission. Wash- ington University now has a special genetic test for patients with his type of leukemia.
Just recently, Solit’s group solved another excep- tional 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 dur- ing cell division. The new one sensitizes cells to the effects of radiation. This patient tumed out to have a mutation in RADSO, 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 muta- tions 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 infor- mation 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 everoli- mus, and 1s planning a new study to test the drug in them. And the original outlier, the woman with blad- der cancer? Three years later, she’s still on everolimus and still having a “complete response,” Solit says. She’s doingfine. ©
kat mcgowan is acontributing editor at Discover magazine and an independent journalist based in Berkeley, Calif., and New York City.
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