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| Archive : Summer
2006 |
WHEN A PATIENT'S GENES EXPRESS THEMSELVES, THEY MIGHT:
Suggest that a certain treatment
is almost sure to work // Signal that heart transplant
rejection is imminent // Advise against chemotherapy // Issue other messages we
don’t yet understand.
Medicine Gets Personal [page 3]
 By Anita Slomksi
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So do treatments that are toxic for patients, which result in about 1,000 U.S. deaths every year. The AmpliChip CYP450 test, a new diagnostic tool from Roche Diagnostics, looks for variations on two genes that determine how an individual will metabolize certain prescription drugs. Physicians can use that information to avoid prescribing doses that may be either dangerously high or ineffectively low.
As encouraging as it is to witness the arrival of tests and treatments, the march of medical progress often seems agonizingly slow for those desperate for a cure. Forty years ago, scientists found the first genetic clue to chronic myelogenous leukemia (CML), a cancer of the blood and bone marrow: One chromosome in the white blood cells was shorter than normal. But it wasn’t until 1987 that scientists identified the protein that the two ends of the broken chromosomes express, Bcr-Abl tyrosine kinase, which produces an excess of white blood cells. In the early 1990s, Novartis was trying to make a drug to combat a gene implicated in coronary thrombosis. Though the therapy wasn’t effective for that purpose, it did block the Bcr-Abl protein. Gleevec (imatinib mesylate) entered Phase I clinical trials in 1998 and was granted fast track approval by the FDA in 2001 after the majority of CML patients responded well with no serious side effects. And so, after 35 years, Gleevec became the first therapy to target the expression of a gene abnormality.
Iressa (gefitinib), approved in 2003, also blocks a tyrosine kinase, but in non-small-cell lung tumors. When it works, Iressa reduces tumors by 50% to 90%. Yet only one in 10 U.S. patients responds to the drug. To find out why, Daniel Haber, director of the Massachusetts General Hospital Cancer Center, looked at the gene producing the protein targeted by Iressa—epidermal growth factor receptor—and found that tumors responding to the drug had a genetic mutation at exactly the site where Iressa would bind to them. The mutation causes the protein to bind to Iressa 10 times more tightly than a normal protein does. That finding, confirmed by other researchers in Boston, New York and elsewhere, helped explain the low overall response rate to Iressa, and provided an approach for targeting the drug to those most likely to respond. It also led to a genomics test that examines DNA from lung tumor tissue to predict which patients will benefit from Iressa.
Now Haber and others are seeking to understand another anomaly—that large percentages of some populations with non-small-cell lung cancer, namely women, Asians and nonsmokers, have the mutation that makes the tumor treatable with Iressa. But for aerospace engineer G.M. of San Gabriel, Calif., the reason hardly mattered. G.M., who is Chinese and who spent the first 18 years of his life in Hong Kong, was devastated when doctors discovered a golf ball–size tumor in his right lung. But his oncologist told him how extremely effective Tarceva (a drug related to Iressa, and preferred in the United States) is for nonsmokers, particularly those of Asian descent. Five months after his therapy began, G.M.’s lung tumor disappeared.
Five years from now, Haber predicts, physicians will prescribe therapies based on a tumor’s critical genes rather than on where in the body the cancer originated, because many targeted drugs are found to work in multiple types of cancers. “Right now we are looking only at mutations in genes producing kinases because it is possible to make drugs targeting those proteins,” says Haber. “As soon as we can make drugs against other types of proteins, researchers will be matching them with genetic abnormalities in those cancer genes as well.”
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Photo by Lee Williams; Photo of Hand: Don Farrall/Getty
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