On Target
A new generation of drugs offers customized cures
But the new one-size-fits-one approach doesn't work perfectly yet, either. Iressa, for instance, helped only 10 percent of patients in one trial, and in the newest, largest set of trials it didn't improve survival, leading scientists to wonder if they are really seeing the target clearly. And several of the diagnostic tests aren't being used in standard practice, for a couple of reasons: First, doctors unfamiliar with genetics don't know about them or don't trust them, and second, insurance companies won't pay for them. They're too new. "Until the issue of reimbursement is settled, these tests are going to have it tough," says Robert Roberts, an expert in the genetics of heart disease and chief of cardiology at Baylor College of Medicine in Houston.
Despite such obstacles, forays into personalized medicine are now possible because of new technologies that are capable of rapidly analyzing the DNA of diseased and normal tissue. Genes come in different flavors, or variants, and those variants can be as small as a change in a single molecule in the massive genetic chain. High-speed computers and DNA filters called microarrays have made it possible to quickly identify these varieties in a gene.
The first step in targeting a treatment is to link a genetic variation to a specific disease. Then the genetic aberration can be matched with a drug that somehow interferes with it. Such is the case with Herceptin and breast cancer. Malignant cells have deranged DNA to begin with. In the case of about 30 percent of breast cancer patients, the derangement takes the form of an overabundance of a gene called Her2. "It's like the Xerox machine inside the cell gets stuck," says Slamon. "It keeps on churning out copies. Once you get over a half-million, you're off to the races."
It's the cell, actually, that begins racing out of control. Those overabundant genes instruct the cell to make huge numbers of receptors on its surface, which in turn snag signaling molecules called growth factors. Growth factors are essential for a cell's normal, healthy functioning. But when a cell grabs a few hundred thousand or more of them, it begins to grow wildly. It divides and divides, rapidly turning into an aggressive tumor that quickly spreads to other parts of the body. Patients with Her2 have a gloomy outlook.
But in the 1990s, Slamon and his colleagues discovered Herceptin, a drug that fit into the aberrant receptor like a hand in a glove. It leaves no room in that glove for circulating growth factors. What makes Herceptin an especially good drug is that it only hits cells covered with this specific receptor, ignoring healthy cells and thus avoiding the shotgun approach of chemotherapy--including the well-known side effects of nausea, hair loss, exhaustion, and cognitive deficits.
Once it was known how the drug works on the cellular level, the next step was to identify patients overwhelmed by the receptors. Fortunately, there is a test that measures the receptor-making Her2 genes. "Without the test, we would have had nothing," Slamon concedes. Herceptin was approved in 1998 for metastatic or recurrent breast cancer in patients with the receptor. At the time, it looked as if the drug shrank tumors or held them at bay for seven months. Today, given in combination with other therapies, that figure is up to 17 months.
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