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Cancer Cells With A Death Wish


Inside the laboratories of the pharmaceutical industry, where even entry-level jobs can require an advanced degree, extraordinary talents often seem ordinary. Still, Stephen W. Fesik stands out. After joining Abbott Laboratories () in 1983, fresh from completing postdoctoral work in nuclear magnetic resonance (NMR) at Yale University, Fesik accomplished more in 13 years than many researchers do in a lifetime. Using an MRI-like device that reveals the atomic structure of molecules in three dimensions, Fesik perfected and patented a technique that Abbott and other drugmakers use to create medications.

Now, as divisional vice-president for cancer research, the 52-year-old Fesik is trying to top his own achievement -- this time in the area of cancer. His goal is to flick on a cellular switch that should cause tumor cells to kill themselves. It's a trick that has stumped scientists for decades. And with no formal training in cancer research, Fesik at first seems an unlikely candidate to achieve it. His experimental compound is just entering the first phase of clinical trials. Now he and his research team must prove through years of tests on animals and humans that it is safe and effective. "We're attempting to do things that have never been done before," says Daniel W. Norbeck, vice-president of global pharmaceutical research at Abbott. "This is risk piled on risk."

Fesik's approach capitalizes on the natural tendency of cells to self-destruct when they become damaged or drift into a part of the body where they don't belong. This suicide mechanism, called apoptosis, malfunctions in cancer cells, allowing them to spread and form tumors. The culprit is a protein that runs amok, blocking the apoptosis process. In a quest that took years in the lab, Fesik scanned 20,000 molecular fragments until he found two that snugly attach themselves to the protein, turning the death toggle back on. In tests on lab animals, Fesik's compound, code-named ABT-737, helped kill lymphoma and small-cell lung cancer cells. "It's absolutely the right way to go," says Dr. Gerard I. Evan, a professor of cancer biology at the University of California in San Francisco. "Fesik is leading the pack."

BIG-TIME COMPETITION

There is no question that Abbott needs ABT-737 to be a hit. The North Chicago (Ill.) company, which is on track to post 2005 sales of $22.3 billion, is funneling much of its $1.75 billion research budget into oncology -- a new and potentially huge market for the company. But Abbott's first try at developing a cancer drug ended embarrassingly. On Oct. 13 the Food & Drug Administration rejected the product, Xinlay, after it failed to slow advanced-stage prostate cancer. Although Abbott has grown through acquisitions and licensing deals, it hasn't produced a blockbuster of any kind from its own labs since 2000, when it introduced Kaletra to combat HIV. "They have not proven at all that they have a competency in R&D," says Matthew J. Dodds, an equity analyst with Citigroup () Abbott also has big-time competition, including Pfizer Inc. (), which earlier this year acquired Idun Pharmaceuticals Inc., a San Diego biotech lab. Idun was co-founded by H. Robert Horvitz, a biology professor at Massachusetts Institute of Technology who won the Nobel Prize in Medicine in 2002 for his discoveries in apoptosis. Indeed, more than 40 companies are delving into this strategy for treating cancer, reports BioSeeker Group, a Stockholm biotech and pharmaceutical research firm.

At another employer, Fesik might never have been considered for such a critical assignment. In his previous job as chief of NMR research, he mapped the molecular structure and shape of compounds to help drug developers find promising leads. A self-described nerd, he also holds a PhD in medicinal chemistry from the University of Connecticut School of Pharmacy. But he has no medical background, nor has he ever managed the animal trials that are key first steps in drug development. So when he was offered his current position in 2000, he hesitated. "I had a cushy job, frankly," he says. "I was good at it. People knew me." After a month of talking it over with his wife, Lauren, and mentors at Abbott, he jumped in. The choice, he says, came down to this: "What would you rather be doing? Developing the next NMR technique or finding new drugs to treat cancer?"

For Norbeck, Fesik's lack of experience was actually a major selling point. "Innovation is often brought about by people outside of a field," Norbeck says. "Their ignorance about the established dogma allows them to do things that others already had ruled out." Fesik's character also made him a good fit for the job. A linear thinker who loves puzzles and reading scientific papers, Fesik is doggedly ambitious and almost singularly focused on solving his next problem. Early on in his career, his wife had to negotiate with him a cutback in his work hours so he would be home at least one weekend day with their three young daughters.

Unlike many scientists, Fesik isn't afraid to own up to his intellectual shortcomings. When the Internet was just taking hold, co-workers spotted him unabashedly reading The Internet for Dummies at his desk. Fesik tackled his new post with similar gusto for learning. He enrolled in a weeklong, brain-bruising course in clinical oncology for doctors prepping for their board certification exams. "Some heads of cancer research might find it embarrassing to admit they need to take a course like that," says James Summers, divisional vice-president for advanced technology. "Not Steve. He's unafraid."

HANDY TOOL

Fesik has been on this path since his boyhood. He grew up in Lincoln, R.I., one of four children of a machinery-parts salesman and a part-time bookkeeper. To instill some worldliness in the brood, his mother spoke French at the dinner table. Fesik discovered early on that his brain was more suited to science. "I'm horrendous at languages," he says. "Science is logical; it makes sense." After earning a degree in chemistry from the College of the Holy Cross in nearby Worcester, Mass., he spent a year teaching high-school science in Maine.

The young scientist found his calling in NMR while in graduate school in Storrs, Conn. NMR is akin to magnetic resonance imaging in miniature. It turned out to be a handy tool for drugmakers because it allowed researchers to better comprehend the structure of the hundreds of thousands of chemicals in their libraries as well as the target sites in human cells that these medicines must fit into, like a key in a lock, to be effective. "He really has changed the way researchers use NMR in drug discovery," says Ad Bax, section chief of biophysical NMR at the government's National Institutes of Health, who considers Fesik a friendly rival.

Now, Fesik must prove that his research tool can result in a marketable product. Fesik first concocted ABT-737 in 1999. But there was a problem: The molecule also stuck to albumen, which is prevalent throughout the body. So the drug was doomed to get sopped up by healthy cells before it could ever reach the cancer. It took Fesik's team two more years to snap together molecular bits, like little Lego blocks, and come up with an alternative that attached only to the target protein and would be neither toxic nor too weak to cause the desired effect.

Fesik already has thought about the third chapter in his career, fantasizing about running a cancer institute or becoming a professor. But first he'll have to show that his drug works on humans. "The ultimate goal, if you get it, is fantastic," he says. "It's interesting scientifically, but more importantly, it could help a lot of people, let alone make a lot of money for Abbott."

By Michael Arndt


Silicon Valley State of Mind
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