The FDA may be paying more attention. Drug companies are joining the rush to stratify patients according to their genes, and they're doing it with the blessing of the FDA, says Edward Abrahams, executive director of the Personalized Medicine Coalition, a Washington-based public-interest group. He notes that in March 2005 the FDA started asking drug companies to voluntarily share information on how specific subtypes of patients respond to the drugs submitted for review. Since then, more than 25 companies have submitted such data.

Not surprisingly, “many drug companies have concluded that they must incorporate genetic tests into their drug trials,” says UCLA's Sawyers. That was his experience with Bristol-Myers Squibb, the maker of dasatinib. There had been a lot of debate about the usefulness of genetic tests in drug development, he says, “but now most parties agree that it's a good thing. The cost of drug development should go way down when you do clinical trials with the right subgroup of patients. You get faster approval, and you can go on to develop more drugs.”

Insurance companies will have to come along as well, to pay for the new gene-based tests, Sawyers contends, “because these tests will guide the treatment. Insurers could avoid paying treatment costs for all patients, when in fact the treatment might help only a fraction of them.” Abrahams adds that “the growing link between therapy and diagnostics” (in the form of gene-based tests) is the key to the future development of personalized medicine. “The tipping point,” he says, “will come when patients refuse to accept what they often get now—trial-and-error medicine.”

Progress against chronic myeloid leukemia (CML), using Gleevec (imatinib) to halt the cancer where it starts—and now the drug Sprycel (dasatinib) when drug resistance takes hold—is “proof of principle” that personalized medicine can work, according to HHMI investigator Gary Gilliland, a cancer researcher at Brigham and Women's Hospital in Boston. “Once it is demonstrated that a specific genetic mutation causes a cancer, as for the BCR-ABL mutation in CML, you can reliably predict that patients will respond to its inhibitors, such as imatinib - and there are rational strategies to overcome resistance to imatinib if it develops.”

In patients with CML, the abnormal fusion gene, BCR-ABL, leads to an overactive form of the ABL kinase, an enzyme that regulates cell growth and differentiation. The abnormal kinase makes white blood cells grow out of control; it is fundamental to the cancer itself. Gleevec, a drug pioneered by HHMI investigators Brian J. Druker, at Oregon Health & Science University, and Charles Sawyers, at the University of California, Los Angeles, blocks ABL kinase activity, and was approved by the FDA in 2001 for CML.

Far more effective than most other chemotherapy because it is targeted so precisely, “Gleevec puts 80 percent of patients into complete remission,” says Sawyers. That is a huge improvement for a disease that was once uniformly deadly. Gleevec was not the end of the story, however, because patients—about 4 percent a year—eventually develop resistance to the drug and relapse. “Three-fourths of patients are still doing well in their seventh year of therapy,” Sawyers says. “But in 20 years, most of them would be expected to relapse.”

Determined to solve this problem, Sawyers teamed up with John Kuriyan, a crystallographer and HHMI investigator at University of California, Berkeley, and showed that patients whose cancer resisted Gleevec had a special subset of genetic mutations that made their kinase too rigid, keeping it in the “on” position at all times (Gleevec binds to ABL kinase only when it's in the “off” position). They began to search for a “sloppier” drug that might bind with the ABL kinase in any position, and Bristol-Myers Squibb turned out to have a good candidate, called dasatinib.

In the June 15 issue of The New England Journal of Medicine, Sawyers announced that dasatinib produced excellent responses in a phase 1 study. So far it has been tested only in patients who relapsed after Gleevec, but Sawyers says, “It may prove even better than Gleevec—it is much more potent and has a broader reach.” In late June, the FDA granted accelerated approval for marketing of the drug under the name Sprycel for CML patients who have relapsed from or cannot tolerate Gleevec. It was also approved for certain patients with acute lymphoblastic leukemia.

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