The worldwide cancer research community this week mourned the death of Judah Folkman, a medical visionary whose breakthrough ideas were ignored in the 1960s and '70s, but have since become the blueprint for revolutionary 21st-century cancer therapies.
His pioneering theory, known as angiogenesis, holds that tumors must create their own blood vessels in order to grow. Treatments based on cutting off cancer's blood supply have supplanted chemotherapy and made the disease a treatable chronic condition for many patients.
By the time Folkman died of a heart attack at 74 on Monday — changing planes on the way to a medical conference in Vancouver — his theory had become the basis for treating a variety of cancers. More than 1,000 laboratories around the world are hard at work building on his ideas, according to the Children's Hospital in Boston Web site, where Folkman did his own research. Colleagues spoke of him with reverence rare for such a competitive field of research.
"I don't think he slept," said Dr. Harold Dvorak, 70, professor of pathology at Harvard Medical School, who got to know Folkman as an intern at Massachusetts General Hospital when Folkman became chief surgical resident there in 1963.
"People came to his lab or called him every day. He had a very large lab. He traveled constantly to conferences. I'm not surprised that he died in an airport."
Folkman is widely considered the grandfather of a new generation of therapies — most notably Avastin, a multibillion-dollar drug made by Genentech — that arrest cancer by neutralizing chemicals that tumors secrete to stimulate blood vessel growth. Such drugs cut off the supply of blood and nutrients to a tumor, halting its growth and sometimes shrinking it. This approach can often turn some previously lethal forms of cancer into manageable chronic conditions.
But the theory that made him an icon in the cancer world was hardly an instant success. When he first advanced the new ideas in the 1960s and 1970s, established scientists ignored or even ridiculed his ideas
"His thinking was ahead of the evidence for much of his career," said Bruce Chabner, 67, clinical director of the Massachusetts General Hospital Cancer Center. Chabner was a student at Harvard Medical School when he became friends with Folkman, who was then a surgical resident. "He believed in the long-term correctness of his theory even when he didn't have the data to prove it. And he had such great passion for cancer research, both publicly and privately, that he had the ability to get a few people to hang in there with him."
Folkman was doing research in the Navy in 1961 when he had his first insight into tumor growth. He noticed that all of the tumors he implanted in human organ tissue grew to exactly the same size. As he explained on the PBS TV show "Nova" in 2001, he expected the size of tumors to be distributed in the bell-shaped curve that occurs throughout biology. When he saw no bell curve, he hypothesized that a common limitation was halting tumor growth. Eventually, he identified the inability to form blood vessels as that common limiting factor.
Unlike medical doctors today, who must choose early on between clinical practice and research if they hope to compete in either field, Folkman trained as a surgeon and worked in the operating room as well as the cancer laboratory until the mid-1980s. As a young surgeon, he was known for his meticulous preparation.
"He would practice operations on corpses in the hospital morgue the night before he had to perform them on patients," said Dvorak, who was an intern in pathology at the time. "Not many surgeons did that. He had to stay late at night and get up early the next morning. He showed unusual care and concern for his patients."
In 1971, 10 years after he began developing his theory, Folkman published a seminal paper in the New England Journal of Medicine. He was still decades ahead of his time. Most established cancer researchers dismissed the theory.
"No one was thinking like him at the time," said Chabner. "Ninety-nine percent of doctors believed you should attack the tumor directly."
This "cytotoxic" approach forms the basis of chemotherapy. "No one was thinking about attacking the environment of the tumor or its blood vessels," Chabner said.
Folkman doggedly pursued his idea for an additional 30 years, even when his applications for government grants were rejected. The ultimate vindication of his view did not come until 2004, when the Food and Drug Administration approved Avastin. But by then Folkman had become well known for Endostatin, an anti-angiogenic drug he developed with EntreMed, a company based in Rockville, Md.
Endostatin was never approved by the FDA, but it became a huge hit with patients who took it in clinical trials. Scott Toner, 38, a risk manager at Fidelity Investments, says he is alive today only because of Folkman's drug.
When Toner was diagnosed with a rare form of pancreatic cancer on Dec. 11, 2000, he was put on Adriamycin for nearly a year. The toxic chemotherapy agent shrunk the tumor. But Toner says the treatment was killing him.
"If I took it any longer I would have destroyed my heart," Toner said.
Toner, who lives in Boston, heard Folkman speak at Beth Israel Deaconess Hospital there in late 2001. A few weeks later he entered the clinical trials for Endostatin. His tumor stopped growing and he recovered the vigor that he'd lost during chemotherapy treatments.
"You can't stay on Adriamycin for three years," Folkman explained in a 2005 interview. "Your bone marrow is burned up. But with Endostatin there are no side effects."
Toner, who was single when doctors diagnosed his cancer, said he decided to get serious about life on the new drug. He married and fathered a child while taking Endostatin.
"You can't become a parent on chemotherapy," Toner said. "You have to wear protection for your partner."
Folkman celebrated Toner's child as gleefully as the new parents. "He was very proud of our son," Toner said. "He called him the first Endostatin baby." Toner took Endostatin for almost four years. He and three other patients used up the last of the supply after the clinical trial ended and EntreMed quit making the drug.
Folkman maintained close ties with EntreMed until his death. In the 2005 interview, he blamed the failure of the drug not on the company, which found the drug difficult and expensive to make, but on FDA reporting conventions. He said that the FDA measures success by tumor shrinkage, a standard appropriate only for chemotherapy agents, and that it needs to develop "language" for the kind of recovery that patients like Toner experienced.
Today, Endostatin is in development in China under the name Endostar, but it is unclear if or how it will be approved in the United States.
Toner is taking Avastin. He and his wife now have a second child.
"I don't know if my daughter is the first Avastin baby," he said. "But I can tell you that I'm looking forward to turning 40. I didn't plan on that when I was on chemo."