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OBITUARIES | Judah Folkman, 1933 - 2008

Pioneer of cancer-fighting tactic

January 18, 2008|Thomas H. Maugh II | Times Staff Writer

Dr. Judah Folkman, the Harvard surgeon who parlayed a chance observation into a bold and controversial new way to fight cancer and a host of other diseases, has died. He was 74.

Folkman was changing planes at the Denver airport on his way to a conference in Vancouver, Canada, when he died Monday of a heart attack, his family said.

Folkman reasoned that tumors could grow beyond a small size only if they stimulated the growth of new blood vessels to supply their cells with nutrients and oxygen, a process called angiogenesis. The logical outgrowth of that reasoning was that blocking the recruitment of new blood vessels could starve tumors into submission, converting cancer into a manageable, chronic disease.

His ideas were disparaged and even ridiculed for more than a quarter of a century before they became widely accepted during the late 1990s. Today, 10 cancer drugs -- including Avastin and Thalomid -- based on his ideas are on the market, at least 50 more are in testing and more than 1.2 million patients worldwide are receiving anti-angiogenic therapy.

Similar drugs, such as Macugen and Lucentis, are also being used to treat macular degeneration, arthritis and other diseases.

"The world has lost a bright light, but his contributions live on in the thousands of researchers he mentored, new treatments that his work spawned and patients for whom he always deeply cared and to whom he gave so deeply of his time and knowledge," said Dr. James Mandell, president and chief executive of Children's Hospital Boston, where Folkman spent most of his career.

Folkman's original inspiration came in the early 1960s, when he was a lieutenant serving at the National Naval Medical Center in Bethesda, Md. He and his colleague Frederick Becker removed the thyroid gland from a rabbit, kept it alive in a glass dish and injected it with cancer cells.

They observed that the tumor would grow only until it reached the size of a pinhead, at which point it contained about a million cells. When the researchers implanted the gland in a rabbit, however, the tumor quickly began growing until it killed the rabbit.

Folkman reasoned that once a tumor reached a certain size, nutrients could no longer diffuse through it to reach the innermost cells, and growth ceased. But placing it in an animal's body allowed new blood vessels to penetrate the tumor and provide sustenance.

At Harvard, he followed up by implanting small tumors in rabbit eyes -- either near the iris, where there was a rich supply of blood vessels nearby, or in the cornea, where there were none. The tumor implanted in the cornea did not grow, while that near the iris did. The researchers could even observe the formation of new blood vessels feeding it.

His paper describing the results and arguing that blocking angiogenesis could halt tumor growth was rejected by several journals before finally being published in the New England Journal of Medicine in 1971.

But critics said his evidence was weak and were skeptical of the findings. Some said that inflammation produced by dying tumor cells was the actual trigger for angiogenesis and that it had nothing to do with tumor growth.

To counter the argument, Folkman implanted a healthy tumor and a dying tumor in rabbit eyes. Only the healthy tumor stimulated angiogenesis.

His theory received a near-fatal blow when other researchers implanted crystals of uric acid near the iris and also observed the growth of new blood vessels, suggesting that inflammation was the culprit.

"That silenced us for a couple of years," Folkman later said. "By the mid-1970s, I thought the critics were right."

It took two years for researchers to show that macrophages, a form of white blood cell, that descended on the eye to ingest the crystals actually secreted a chemical that recruited new blood vessels.

In 1983, Folkman's group made a major breakthrough. Working in his lab, Michael Klagsbrun and Yuen Shing identified a chemical secreted by tumors that triggered blood vessel formation, calling it "tumor angiogenesis factor," or TAF. Researchers have subsequently found at least 14 other chemicals that do the same thing.

Two years later, the group achieved another breakthrough when an airborne fungus accidentally landed on a laboratory dish in which researchers were growing blood vessels. Working with the fungus, Donald E. Ingber isolated the first angiogenesis inhibitor and showed that it could halt tumor progression in mice. It did not make it to human trials however.

In the mid-1990s, Folkman and Michael O'Reilly isolated two extremely powerful inhibitors, called angiostatin and endostatin, that totally blocked tumor growth in mice. Other researchers were initially unable to duplicate their findings, however, a problem that Folkman attributed to the extreme complexity of the molecules.

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