The Maker of a Miracle Drug

Dr. Brian Druker found a way to defeat a rare leukemia. The result was the miracle drug Gleevec. Now, Druker hopes to build on his success

For Dr. Brian Druker, innovation requires putting up with grueling work hours and taking some big risks. "In science, most things are not very likely to work," explains the tall, slim researcher. "But there are some that would be so incredible that you have to take a leap of faith and give them a try."

That certainly describes Druker's own crowning achievement, the revolutionary drug Gleevec, now a $3.6 billion per year blockbuster. Druker didn't actually invent the drug, but it would never have made it to the market — and to patients — without him. An advance like Gleevec "only comes along once in 10 lifetimes," says cancer center consultant Dr. Joseph Simone. "The way Brian stuck with it when people said it was a blind alley and got it into clinical testing was amazing."

The story begins in the early 1990s. Trained as an oncologist, Druker had seen how chemotherapy often makes patients sicker rather than better, and figured there must be a better approach. He knew that a rare form of cancer called chronic myelogenous leukemia (CML) is caused by a rearrangement of genes that, in turn, results in a faulty enzyme (a type of protein) in blood cells. Why not knock out the enzyme with a drug and kill the cancer cells, Druker wondered?

Deadly Aim

No way, most scientists said. In the first place, blocking the enzyme probably wouldn't stop the cancer. Besides, the body has scores of similar enzymes, known as kinases, that are essential for normal functions. A drug that knocked out the faulty kinase in CML would probably also hit all these "good" kinases, with deadly consequences. Forget trying to target kinases, Druker's advisers said.

Druker persisted, but his career stalled. Despite working 80 hours a week or more at Harvard's renowned Dana-Farber Cancer Institute (and having his first marriage fail as a result), he was turned down for a key promotion. "I was told the job was given to someone with more promise," he recalls. "It was like someone knocked me in the head."

The setback turned out to be a blessing in disguise. "I needed to get my own lab and have someone believe in what I was doing," Druker says. He found both at the Oregon Health Sciences University in 1993. He also persuaded researchers at drug company Ciba-Geigy (now Novartis) to let him test kinase-blocking compounds that company chemists had created. Within weeks, he found that one of those chemicals killed leukemia cells without harming normal cells. After additional studies showing that the drug appeared safe, he wanted to try it in patients.

Not so fast, Ciba-Geigy responded. The company didn't want to take a chance on an unknown Oregon scientist, and it also feared the drug would be both toxic and ineffective. More important, company executives saw no profit in a drug for a rare cancer like CML. "The marketing people saw just 5,000 patients [being eligible], so of course there was resistance to developing the drug," says Paul Herrling, head of corporate research at Novartis.

Again, Druker persisted. "It was a five-year crusade to get this drug to patients [in clinical trials]," he says. When he did, the results were almost miraculous. "It was absolutely incredible to live through this, and see patients who were told they had very little time left and to get their affairs in order all of a sudden have their blood counts return to normal," he recalls. "The black cloud over them lifted, and their hopes returned. I still get chills talking about it."

Wider Applications

The stunning responses in the trials got Novartis' attention. It also helped that the drug turned out to hit faulty kinases linked to other cancers as well as the enzyme that causes CML, expanding the potential market. Novartis put the drug's development on the fast track, and the Food & Drug Administration approved it in 2001. Now, it's one of the company's best-selling drugs.

With Gleevec, Druker proved it's possible to stop cancer by targeting the genetic defect that causes the malignancy in the first place. That success led to an explosion of similar efforts in other cancers. Perhaps just as important, adds consultant Simone, Gleevec's development has changed the practice of science. There once was a vast gulf between basic scientists toiling in the lab to understand genetics and biology, and clinical researchers testing new treatments on patients. Druker bridged that gulf. "That had an enormous impact, changing the attitude of cancer researchers towards clinical applications," Simone says.

Druker's work is far from done. For all its powerful effects, Gleevec is a not a cure. Because some malignant cells are resistant to its effects, the cancer eventually returns in most cases. To make what he calls "the next quantum advance, going from remission to cure," Druker is searching for other potential weak spots in the cancer's defenses. He's systemically looking for potential drugs capable of targeting some of the other 500 known kinases, which could play roles in CML and other cancers. "I always come back to leukemia and kinases," he says. "I find I make the most progress when I focus on what I do best. If there is a secret to success, it's understanding what your talents are and following them with a passion."

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