Cure Crusader

By Dick Thompson/Washington

Floyd Nichols was indomitable. He was only 19 when he was found to have a rare, lethal form of cancer that required the removal of his colon. But the young Chicagoan finished college, in spite of the additional burden of dyslexia, and became a successful computer salesman before starting his own mainframe business. By his mid-30s, he sold it off to begin what his family and friends thought would be a leisurely early retirement. When he told them he would cure cancer instead, they just laughed. How could a layman--even a wealthy one--do what had stumped even highly skilled scientists with Ph.D.s?

Ten years after he started his crusade--and three years after his death--they have their answer. The drug that Nichols championed has shown such promise that the Food and Drug Administration has put it on a fast-track review. A decision on its use could come any day.

Nichols' story is remarkable. He not only fought for the drug's development in the face of total disinterest by drugmakers and mainstream cancer scientists but may also have opened the door to a whole new family of cancer drugs. Says Dr. Francis Giardiello, chief of gastroenterology at Johns Hopkins: "He spurred them to look into this a lot deeper and a lot faster than they would have otherwise. He has a proud legacy." He may also posthumously save the life of his son.

The disease that struck Nichols as a teenager was familial adenomatous polyposis (FAP), a genetic disorder characterized by a wild--and potentially lethal--growth of cancerous polyps on the inner lining of the intestine. The only recourse is to remove them surgically, along with the intestinal wall, and outfit the patient, at least temporarily, with a waste-collection bag strapped to the body. Nichols desperately wanted to protect his son from that grim experience.

His determination increased when at age 35 he learned that his disease had returned. This time doctors recommended immediate--and even more serious--surgery: removal of parts of his stomach and small intestine. Although physicians told him there was no alternative, Nichols stubbornly decided to find one. Says his sister Elizabeth Troy: "He believed anything could be done. Failure was never an option, ever."

He began reading the medical literature and calling scientists. Eventually he talked to Dr. Randall Burt, now the chief of gastroenterology at the University of Utah. Coincidentally, Burt had just heard University of Colorado surgeon William Waddell tell a scientific meeting that he had seen an aspirin-like arthritis drug called sulindac (Merck) almost miraculously melt away colon polyps. The finding was anecdotal, observed in only a few patients, but it was just what Nichols wanted to hear.

He promptly informed his doctors at the University of Chicago that he would try the drug. Almost unanimously they advised against it; one called the idea suicidal. Besides, it could produce severe side effects. But Nichols took the drug anyway--and it eliminated his polyps.

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.

In 1995, Nichols' company finally began testing FGN-1 on humans. In a trial of 18 patients with FAP, 12 showed substantial improvement. One patient, who was developing about 100 polyps a year, had no polyps at all while on the drug. This led to another, larger double-blind study with one group taking a placebo, the other FGN-1. But midway it was discovered that the recruitment of patients had been mishandled and a year's worth of work was lost. Still, Nichols could see that in a core group of subjects the drug was working as he had hoped. He had nearly completed bringing a drug through the rigorous trials required by the FDA for roughly one-tenth the amount usually spent by the industry powerhouses.

But just as he seemed on the verge of a great success, Nichols began losing weight. This time the diagnosis was stomach cancer. Nichols launched into a search for yet another treatment. But the malignant cells were too aggressive. "He just finally realized he wasn't going to come back from it," says Lynn. Nichols died in May 1996, at 43, but by then he knew the work was probably well enough along on FGN-1 for it to be there for his son and other kids.

Last year Cell Pathways began tests on children. The first child to be enrolled in the study was Eric Nichols, 11, who had been found to have his father's disease. Other studies are showing that related drugs may be effective against a broad range of cancers, including colon cancer, the No. 2 cause of cancer deaths in the U.S.

Eric, whose disease seems to have been contained by the treatment, expresses awe of his father's achievement as only a youngster would. Says he: "It's a really cool thing." No one is likely to disagree with that heartfelt opinion.