On Target
A new generation of drugs offers customized cures
Reprieve. Ginger Empey started the drug in 1995, as part of a clinical trial. Her cancer had spread to her liver, chemo had failed, and her oncologist told her to get her affairs in order. "So I fired him!" Empey says. "It felt like getting hit with a sledgehammer. You can't help but hate a person who delivers a message that way." But she'd heard about Herceptin and banged on doors at UCLA until they tested her and found she was Her2 positive. She started the drug, and within months her tumors had shrunk to next to nothing. Today Herceptin still drips in, every three weeks, through a tiny tube implanted in her chest. "This is my 385th week on the drug. But who's counting? Look, people with my kind of cancer aren't supposed to live very long. I've already passed that. I really hope I'm the one who's going to make it out alive."
Not everyone does, of course. The drug seems to help about 40 percent to 50 percent of those who take it. "So clearly, we're not at the end of the road with it," says Mark Pegram, a UCLA oncologist. "We have to find new approaches for the nonresponders."
Those same sentiments are voiced by researchers who work on Iressa, the lung cancer drug taken by Gloria Caruso. "I've seen some remarkable things with patients on this drug," says Alan Sandler, an oncologist at Vanderbilt University Medical Center who worked on some of the early Iressa tests. "One woman came in a wheelchair. She couldn't even get dressed because her body was filled with fluid from the cancer. I would have given her a few weeks. But in a few weeks, on the drug, she was up and around. MRI images confirmed that her lesions shrank." Then there's Caruso, on the drug for 23 months--it's one pill, once a day--and still going strong. "My neck tumor was supposed to swell and cut off my air," she says. "Now, it's disappeared."
Fuzzy target. But Caruso is in the fortunate, small minority who get such positive results from Iressa. Unlike Herceptin, Iressa has no test that identifies patients most likely to benefit from it. Indeed, many scientists argue that it was a mistake to push Iressa ahead without such a test, because it's basically a targeted drug without a clear patient to target.
The drug's maker has a sharp retort: "That's insane!" says Mary Lynn Carver, a spokesperson for AstraZeneca. "That's saying, `Let's wait until we have everything tied up with a nice neat bow before we save somebody's life.' In lung cancer, people usually die within a year of diagnosis. You can't wait if you want to save people like Gloria Caruso." The gene analyzers are busily churning through tumor samples, searching for a difference between responders and nonresponders that could refine the target. Meanwhile, the drug may be approved next month as a last-ditch therapy.
Given the difficulties of developing new drugs, some of targeted medicine's pioneers have turned to diagnostic tests instead (box, Page 56). For example, a drug that's often used to prevent organ rejection after a transplant is broken down by an enzyme called TPMT. This prevents the drug from reaching toxic levels in the body. However, Bill Evans of St. Jude Children's Research Hospital in Memphis has found three genetic variants in TPMT that essentially cripple it in 1 of every 300 people. People who have these variants must take much lower doses of the transplant drug, because the normal doses could be fatal. A genetic test to identify those people has become standard in the transplant field. "It's made its way all the way from the lab to the bedside," Evans says.
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