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Pioneer of cancer-fighting tactic

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.

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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.

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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.

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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.

Their findings received little attention until 1998, when a New York Times reporter, recounting a dinner-table conversation by Nobel laureate James D. Watson, quoted him as saying that “Judah Folkman is going to cure cancer in two years.”

Folkman was deluged with interview requests and as many as 1,000 phone calls and e-mails a day from patients seeking the drugs, which hadn’t been tested in people. He tried to downplay the interest, noting, “If you have cancer and you are a mouse, we can take good care of you.”

Ultimately, critics were able to reproduce the Folkman lab’s findings, but clinical trials of the two compounds have not yet revealed any unusual anti-cancer activity.

Several other anti-angiogenic compounds discovered elsewhere have been licensed for use against cancer, but none has proved as effective as Folkman had originally hoped. Nonetheless, as many as 100 research laboratories are searching for new drugs that they hope will be better.

Moses Judah Folkman was born Feb. 24, 1933, in Cleveland, the son of a rabbi. He, his brother and sister often accompanied their father on hospital visits to sick congregants. Although his father wanted him to become a rabbi, he concluded that he could do more good as a physician. His father then told him that he should become “a rabbi-like doctor.”

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Folkman’s interest in science developed early. His grandfather had intended to present him with a Jeep for his bar mitzvah, but young Judah persuaded him to purchase an expensive microscope instead, which he used to set up a laboratory in his basement.

For a high school science project, he was able to keep a rat’s heart beating outside its body for 30 minutes using a device made from a toy refrigerator and a bicycle pump.

Folkman was a pre-med student at Ohio State University, developing an interest in cancer research and co-publishing several scientific reports about new ways to treat liver cancer. He graduated with honors in three years and enrolled at Harvard Medical School at the age of 20.

He was known as a hard-working, dedicated and compassionate physician who would stay after his shift to comfort a patient or family member in need, and he often gave patients his phone and pager numbers.

After graduating magna cum laude in 1957 and performing a residency, he went to the naval center in Bethesda, where he did research on alternatives to whole blood for transfusions.

He also worked on the development of “artificial glands” made of rubber that would release hormones slowly like a real organ. That effort eventually led to the manufacture of implanted birth control devices like Norplant.

Throughout Folkman’s career, the skepticism of other scientists made it difficult for him to receive federal funding for his research, so he sought alternatives. In 1974, he received a 12-year, $23-million grant from Monsanto -- by far the largest such grant a Harvard scientist had ever received. He was criticized for that as well, but was backed by the school’s administration. He also received a $40-million grant from Entremed for the development of endostatin.

In 1981, he decided to give up his position as chief surgeon at Children’s Hospital and was named director of the hospital’s Surgical Research Laboratories.

“He didn’t have the love” of the operating room “that a lot of surgeons have, and that led him to step down as chief,” said Dr. David G. Nathan, president emeritus of the Dana-Farber Cancer Institute. “He wasn’t as interested in technical surgery, but he was a master of inquiry into how the body works.”

During his career, Folkman wrote more than 400 peer-reviewed papers and more than 100 book chapters and monographs and received a plethora of honorary degrees and awards.

He is survived by his wife of 47 years, the former Paula Prial; a brother, David, of Hillsborough, Calif.; a sister, Joy Folkman Moss of Rochester, N.Y.; daughters Laura Folkman Steuer of Menlo Park, Calif., and Marjorie Folkman of New York City; and one granddaughter.

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thomas.maugh@latimes.com


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