Cure Crusader

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Nichols began calling pharmaceutical houses in the U.S. and Europe, telling them that if they started making sulindac it would save thousands of lives. But it was about to come off patent, and as a generic drug it didn't offer much of a payoff because of the likelihood of competitive products and lower prices. Moreover, FAP--Nichols' cancer--is a so-called orphan disease, afflicting only 25,000 Americans, so there wasn't much of a market for it. Thanks, but no thanks, the drugmakers said.

"He was really, really angry," recalls his wife Lynn, because he knew it could keep kids, possibly his own son, from the horrors of surgery. "He said, 'If they won't do it, I will.'"

Although bringing a new drug to market can be time-consuming (up to 15 years) and costly ($500 million), Nichols was undaunted. In 1989 he started his own pharmaceutical company, Cell Pathways, with Dr. Rifat Pamukcu--the lone physician at the University of Chicago who had supported his decision to forgo surgery--as chief scientific officer. At first, Nichols used his own money, then he turned to friends, and finally he sold off shares to venture capitalists, eventually raising $81.5 million but leaving him with only an insignificant interest in Cell Pathways. Getting rich was never his goal.

Instead, he set out to "find the essence of the drug" and remove the side effects. When Pamukcu arranged for scientists at the University of Arizona to take on the research, Nichols moved to Tucson to help oversee their work. The scientists determined that the body breaks down sulindac into two components, but then got bogged down in a debate about which of these components to pursue. After listening to the pro and cons, Nichols decided for them--they would explore both chemical pathways. In the test tube, one compound quickly proved to be superior. "It was killing all the cancer cell lines we were throwing at it," says Pamukcu.

Encouraged, Nichols' scientists began testing the compound, designated FGN-1, on lab animals. It seemed effective against several types of cancers--breast, lung and bladder--but the animals lost weight. That raised a question: Was it the drug or the weight loss that was providing the anti-cancer action? When the scientists repeated the experiments at lower doses, the animals improved without losing weight. "We got a beautiful dose response," says Pamukcu.

Still, Nichols wanted to know how FGN-1 worked. Until then, colon cancer was thought to be a disease of uncontrolled growth. Nichols' scientists suspected instead that the problem was uncontrolled death. Cells lining the intestines usually live only 72 hours. But while cells are born at the usual rate in FAP patients, some fail to self-destruct, producing an excess. Johns Hopkins' Giardiello eventually showed that drugs like sulindac work by restoring the natural process of cell death in the colon. Precisely how it does that, however, remains unknown.