Experimenting With Drugs
The next step to therapy comes in finding the drugs that will work just as specifically, fingerprint by fingerprint. That is the work of Harlan Waksal, whose biotech company, ImClone Systems, has been the focus of controversy this year after seeking FDA approval for a promising anti-colon cancer drug.

A native of Dayton, Ohio, Waksal, a pathologist, double-majored in biology and philosophy at Oberlin, followed by medical school at Tufts University. He quickly found himself itching to do more. "I wanted to do something that would have a greater potential benefit," he explains. "That comes out of a philosophy I gained at Oberlin."

In 1984 he partnered with his brother, Samuel, who had a PhD in immunology, to launch ImClone Systems in Manhattan. With Harlan as its chief operating officer and Samuel trying to woo venture capitalists, the pair struggled at first with their mission: to research and develop experimental drugs relating to the immune system.

With truckloads of persistence and a bit of luck, the Waksals obtained a novel drug that represented a new breed of specific anti-cancer agent. In 1994, ImClone researchers began injecting the drug C225--now dubbed Erbitux--into their first cancer patients, people who had reached the last stages of colon cancer after failing two other types of chemotherapy.

Erbitux, says Waksal, targets the cells of solid tumors by gumming up the receiver of the "on" signal. Normally, he explains, cell division is regulated by two opposing systems: "on" and "off."

"Inducing a cell to divide is a lot like getting your car to go," Treichel says. "You need to give it a series of "on" signals. A driver must key the ignition, put the car in gear, and press the accelerator--the "on" signals. But to drive a car, one must also release the parking brake, an "off" signal. The balance between the on-off system in cells is crucial.

"Cancer cells violate that balance," she adds. "They divide according to their own agenda."

The reason has to do with mutations. Cells turn cancerous in a cumulative fashion. A person might be born with or acquire a mutation in one or two "off" signals. The cell is not yet cancerous, but simply more prone to divide. Over time, a person's cells might accumulate even more mutations, perhaps through lifestyle choices. Smoking might cause cells to gain genetic alterations in the remaining "off" signals, in essence killing the brakes on cell division.

Cancer researchers have spent decades trying to come up with drugs that either reapply the brakes or force wayward cells to commit suicide in a biochemical process known as apoptosis. But ImClone researchers had another idea: to wipe out the "on" receiver that tells the cancer cell to divide wantonly, says Waksal. Erbitux targets the "on" receiver called the epidermal growth factor receptor, which is found in abundance in many solid tumors such as those of colon, head, and neck cancers. Tumor cells actually produce more of this receptor compared to normal cells because cancer cells want to fuel their own reproduction. "With Erbitux, we are reintroducing a check to cell division," Waksal says.

Early studies seemed to bolster Waksal's case. In October 1999, ImClone launched a study of 125 patients with colon cancer who had failed treatment with a chemotherapy agent called Irinotecan. Erbitux, when given intravenously in combination with Irinotecan, shrunk the tumors in 27 patients by half; in the oncology world, that's a 22.5 percent response rate. A later clinical trial of 40 patients with pancreatic cancer also turned up promising results. The tumors in five patients shrunk by half, and the cancers in 16 others either stalled in growth or showed some response to the drug when given in combination with chemotherapy.

This seemed unusually promising for such sick patients, especially for those with pancreatic cancer which is typically untreatable, but the FDA in January refused to consider ImClone's application to sell the drug. Reportedly, the agency was critical of some aspects of the clinical trials--including whether enough patients had been tested and if the original patients were actually as sick as reported. Also questioned was a lack of information on the drug's side effects. Still, the Waksal brothers and other researchers are confident that the FDA's concerns will be addressed and that the application will be accepted for review within the year. Trials with similar drugs are under way with pharmaceutical giants AstraZeneca and Genentech.

"This is my crystal ball," says Waksal. "I hope we can turn cancer into a chronic type of disease where we can keep people alive with a good quality of life, in spite of the problems." This would be far better news than an imminent death sentence to patients with aggressive cancers or those in later stages of spreading.

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