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Gathering Speed

With one out of every two men and one out of every three women in the United States likely to get cancer at some point in their lives-and about 560,000 Americans expected to die of the disease this year alone, according to the American Cancer Society- advances can’t come fast enough. As many as 500 research laboratories in academia and industry are already employing DNA chips to develop sweeping new genetic pictures of different cancers. In 1999, the National Cancer Institute alone provided $4.1 million to 24 U.S. academic cancer institutions to set up or upgrade microarray centers.Meanwhile, the pharmaceutical and biotech industries are drawing on information gleaned from DNA chips to develop new and better diagnostic tests and more effective anticancer drugs with fewer side effects. Indeed, all the major drug companies and at least a dozen biotech firms are already using DNA chips to tackle cancer.

At the same time, large manufacturing companies such as Agilent Technologies, Corning and Motorola are seeing the potential of DNA chips. All three have allied with academic research centers to come up with DNA chips that will analyze genes related to specific cancers. And while at the moment DNA chips are far too expensive to compete with existing diagnostic technologies, the involvement of these manufacturers and their production facilities could drop prices as low as $10 for a chip, once large-volume production gears up.

Of course, for DNA chips to help win the war on cancer, it will take considerable effort-and years of further development. For one thing, DNA chips generate tons of data, and researchers will need to beef up their computing capabilities and nail down data standards in order to make sense of it all (see “Gene Babel,” TR April 2001). And any new drugs or diagnostic devices will have to prove themselves in clinical trials. But the initial fruits of the efforts to apply DNA chips to cancer-new diagnostic tools-could begin saving lives as early as the end of next year. The first anticancer drugs developed using DNA chips will enter human trials around the same time, with dozens more to follow. With all those new tools available, currently untreatable forms of cancer may, one day, no longer mean death sentences.

Profiles in Cancer

The first step toward that grand vision is generating a profile of the genes that are activated or shut down when a normal cell becomes cancerous.While most genes are quiet in any given cell at any given time, the ones that are active, or “expressed,” tell a lot about that cell’s health.And though many of us tend to think of diseases as being caused by particular genes-say the gene for Huntington’s disease or cystic fibrosis-most diseases actually involve complicated interactions among a large set of different genes. However, just as a person’s fingerprints can be distinguished from virtually all others by just a small number of differences, a sort of genetic fingerprint, perhaps involving a hundred active genes or even fewer, could distinguish cells showing even the very earliest signs of cancer.

The beauty of using a technology like DNA chips to find those fingerprints, says Klausner, is that “we’re not limited by preconceived knowledge or notions.” In other words, cancer investigators no longer have to bias their experiments by looking individually at the genes they suspect might be involved with a particular cancer. “Instead of focusing on one gene,” explains National Cancer Institute researcher Louis Staudt,”with microarrays we get to look at the entire genome and let the cancer cell tell us what the important genes are.”

The flagship in the National Cancer Institute’s efforts to demonstrate the validity of the DNA-chip approach is the so-called Lymphoma/Leukemia Molecular Profiling Project, which is directed by Staudt. The study is looking at diffuse large B-cell lymphoma, a relatively common cancer of the white blood cells that affects more than 15,000 people in the United States each year. When oncologists give those patients standard chemotherapy treatments, about 40 percent respond rapidly. Their cancer melts away, and the majority are still alive five years after diagnosis. But of that other 60 percent, most are not so lucky. The cancer may go into remission briefly, but when it returns, it comes back with a vengeance. A few patients benefit at that point from radiation treatments and bone marrow transplants, but for most it is already too late to halt the spread of the disease. Clearly there is something different about the two groups, but under a pathologist’s microscope their cancer cells look identical.

The surprising answer is that these patients respond differently to treatment because, in fact, they are suffering from completely different types of lymphoma. Using what they dubbed a “Lymphochip,” a customized Affymetrix DNA chip, Staudt and a group at Stanford led by geneticist David Botstein discovered distinctive genetic differences between the cancers in the patients with large B-cell lymphoma who died and those who survived. “I was blown away by what we found,” says Botstein. Effectively, they were looking at two different illnesses. “It’s remarkable,” says Staudt. “We found something in this disease that was missed for all the years pathologists were looking at it.”

Similar projects are now under way to profile various forms of cancer, from different types of melanoma to colon cancer. Most other cancers present pictures similar to that of lymphoma: some patients get better and some do not, but predicting who will respond to therapies is impossible. If there were some way to identify the patients who won’t respond to standard chemotherapy, doctors could turn immediately to alternative treatments-and save lives. Indeed, says Pat Brown, a Stanford University School of Medicine geneticist who helped invent one of the two main types of DNA chips, “The same story is coming out for a bunch of cancers we look at-cancers with different clinical outcomes have different molecular subtypes.” And knowing the precise subtype of cancer afflicting a patient could help doctors pick the right treatments, right from the start.

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