Brave New Pharmacy

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But Tepper's group wants to go a step further, identifying the one or two or three receptors common to all the major cancers--breast, prostate, lung and colon--and thus create a one-stop superdrug. Before the genome was available, this would have been almost impossible. Now Millennium scientists can take known genetic fragments of cancer-cell receptors and plug them into the genome database posted on the National Institutes of Health's GenBank website, searching for sequences in the genome that match and eventually getting to the genes that regulate cell-surface receptors. Almost immediately, they were able to discard as irrelevant some 23,000 of the genome's 30,000 or so genes.

Subsequently the researchers at Millennium had only 7,000 genes to sift through for those specifically active in cancer cells. For that they needed to compare the gene sequences with living cancer cells. That's where Zeus came in: after its custom-made microarrays had marinated for 18 hours in the genetic stew from human tissue cells, technicians scanned them to see which bits of DNA lighted up the brightest with radioactive dye. By comparing the cancer-covered arrays with those immersed with normal cells, the scientists could see which receptors were active in all the cancers yet inactive in normal cells--in this case, just 200 of the original 7,000. "These are experiments that we could only dream of but could never do before the genome," says Tepper.

But they still had too many targets for drug designers to deal with. To narrow the possibilities further, Millennium scientists took breast-cancer cells from two dozen patients and ran additional array screenings to get a better idea of how prevalent a particular receptor was on breast-cancer cells in the population at large. Then they focused on the most widespread and active among them. That brought the hundreds of choices down to just a few dozen, among which are a handful that are expressed in more than 80% of patients.

In just three months, Millennium had finished a winnowing process that would once have taken five or 10 years. Says Tepper: "Drug discovery could never be done this way before. You wouldn't know that a drug was effective or potentially effective in a given percentage of your patient population until very late in clinical development."

Once genomics has identified a potential target protein on cancer cells, scientists still have to find or create a compound--the monoclonal antibody--to lock onto that target and block its normal activity, or at least stick a red flag on it to make it vulnerable to destruction by the body's immune system. At this point, Millennium's process finally begins to look like the "wet lab" that drug companies have relied on for decades. To come up with a monoclonal antibody to fight cancer, Tepper's group uses a strain of mice whose immune systems are genetically engineered to generate human antibodies. Choosing whichever receptor protein Zeus has found for them, the scientists inject the mice with it, then extract the antibodies the animals create to fight the invader.