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Dosages of the new drug were fine-tuned for each patient based on detailed studies that examined how well the drug inhibited its target—a technique that was pioneered by Sawyers's group for use in earlier studies in mice. In addition, each patient's resistance-enhancing mutation was sequenced by Bristol-Myers Squibb scientists. This allowed the researchers to correlate how the drug responded to each type of mutation.
“Every single patient who was predicted to be sensitive to dasatinib based on the genotyping studies had a clinical response,” Sawyers says.
This shows that all CML patients could be genotyped (have their genes analyzed) to decide whether their condition will respond to these molecularly targeted drugs. Genzyme's new BCR-ABL Mutation Analysis test is already available to physicians, Sawyers notes, and “in leukemia, the tumor is in the blood, so it is easy to test for.”
The current gold standard for colon cancer detection is colonoscopy, an invasive and unpleasant procedure that many people avoid. The more widely used fecal occult blood test, designed to detect blood in the stool, catches only about 30 percent of colon cancer cases. Malignant tumors do not always bleed.
For the past decade, HHMI investigator Bert Vogelstein and his colleagues at the Johns Hopkins University School of Medicine have sought ways to detect specific alterations of DNA in patients with very early colon cancer—first in the patients' stool cells (one test he developed to detect DNA alterations in stool samples became available in 2003), and now in blood.
“In colon cancer, the genetic mutations are well known,” points out Vogelstein, who played a major role in discovering them. So he began the ambitious project of looking for fragments of the cancer-causing gene, adenomatous polyposis coli (APC), in samples of blood. With the aid of a technique called BEAMing, in which DNA fragments of a cancer gene are attached to metal beads and amplified, he found tiny samples of APC in blood drawn from patients with colon cancer. He has evidence that such fragments are released into the blood when white cells destroy dead tumor tissue.
Pilot studies of Vogelstein's experimental blood test showed that it easily identified people with advanced colon cancer and could even detect more than half of those whose cancers were in the early stages at which they could be cured by surgery—without the need for chemotherapy. “We could still find fragments of the mutant DNA in their blood, but fewer of them,” says Vogelstein. “They were detectable in more than 60 percent of the early-stage patients.” This could save hundreds of thousands of lives every year among people who do not undergo colonoscopies. He hopes the test will eventually become more sensitive; more advanced versions are being developed. Vogelstein expects patient compliance, once the test becomes available, to be much higher than for other tests, “because most patients routinely have blood drawn when they visit their physicians.”
He adds, “This type of blood test might apply to other early cancers, as well. That's one of the reasons we're excited about it.”
Joan Massagué, an HHMI investigator at the Memorial Sloan-Kettering Cancer Center, has been analyzing what makes a particular cancer spread to other organs. Because such “metastasis” is what actually kills people, understanding what provokes it is obviously a high priority for researchers. In 2003, Massagué and his colleagues discovered that cancer cells that spread from breast to bone express certain genes in an unusual pattern. And in July 2005, the scientists reported that breast cancer cells invading the lung also express their own unique “gene signature.” Only 6 of the 95 genes in the lung-seeking cells overlap with those in the bone-seeking group.
“By now we have moved beyond markers of poor prognosis and have identified some of the genes that are the keys to the disease—that actually cause metastasis to a particular organ,” says Massagué. Because many drugs already exist that can block specific genes, “If we can inform physicians about the genes involved in metastasis to the lung, for instance, they can try various combinations of drugs to counteract these genes' activity,” he adds. His team has used this approach in mice with success. Blocking three or four of the genes involved in metastasis to the lung prevented the cancer's spread “almost totally.”