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February 26, 2004


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HARVARD GAZETTE ARCHIVES

Ronit Satchi-Fainaro, Judah Folkman
Young chemist Ronit Satchi-Fainaro (left) was asked by venerable cancer researcher Judah Folkman to solve a problem. She did. (Photo special to the Harvard News Office)

Cancer drug given new life

Its toxic side effects eliminated

By William J. Cromie
Harvard News Office

The cancer drug's effectiveness surprised everyone. Called TNP-470, it stunted the growth of every malignancy it touched - animal tumors, human tumors, and spreading tumors. It suppressed tumors of the ovaries, colon, prostate, and breasts. In some cases the tumors shrank; in others, they disappeared.


Video:

Judah Folkman talks about cancer as a manageable disease

But it was too good to last. Some patients whose malignancies were repressed, even eliminated, started showing unacceptable side effects - problems with motor coordination, seizures, and malaise.

TNP-470 was developed by Donald Ingber and Judah Folkman of Harvard Medical School, two of the best in the business of cancer research. Folkman, Andrus Professor of Pediatric Surgery and professor of cell biology, had discovered that cancers could be starved to death by cutting off the growth of blood vessels they depend on for nutrition. In his laboratory at Children's Hospital in Boston, he and his colleagues produced several drugs that stifled the growth of such vessels. TNP-470 seemed to be the most effective.

Avastin approved by FDA

Avastin, a promising new drug to treat colon cancer, was approved by the Food and Drug Administration (FDA) on Feb. 26. It is the first drug approved to fight cancer by blocking the growth of blood vessels that tumor cells rely on for survival.

The idea of killing tumor cells by choking off their blood supply was first proposed in 1970 by Judah Folkman of Harvard Medical School and The Children's Hospital in Boston. The concept was at first ridiculed as absurd by cancer specialists. Later, when these drugs were shown to be efficient killers of tumors growing in both animals and humans, they were overhyped by the media as a cure for all cancers. The FDA approval supports Folkman's position that such drugs are a valuable addition to the arsenal of cancer weapons, and that, given along with other treatments, they can prolong the lives of many patients.

The FDA approval "is a turning point in cancer therapy and a landmark development in more than 30 years of research," Folkman said.

Avastin is currently being tested for its ability to kill other types of tumors, including breast cancers. Drugs developed in Folkman's lab to both choke off and promote the growth of blood vessels are under investigation to treat a wide range of medical problems including heart disease, one form of blindness, and psoriasis.

"It's a wonderful drug," Folkman comments. "It inhibits growth of the largest variety of different tumor types of any drug yet tested. It works on metastatic (spreading) tumors. It's rare that a drug does that."

So the side effects were a crushing setback. Folkman discussed the problem with Ronit Satchi-Fainaro, a young chemist he recently hired as a research fellow. "I can fix the problem," she told him.

Satchi-Fainaro realized that TNP-470 molecules are too small. They slip easily into leaky new blood vessels growing into tumors; that's what made the molecules so effective. But they also penetrate healthy cells. The researchers found them in the spinal fluids of test animals. Their assault on nervous tissue was interfering with motor coordination and producing seizures. Her solution: bulk up the molecules; make them too big to get into any place but the tumor blood vessels.

It sounded too simple. But, Folkman admits, "Ronit knew more chemistry than I did. That's why I hired her." He told her to go ahead.

A big surprise

The idea worked. The jumbo drug technically known as the new conjugated TNP-470, slows the growth of deadly skin cancer (melanoma) and lung tumors in mice. Unlike free TNP-470, it's too big to have toxic effects on the nervous system. The motor coordination of the mice is fine and they develop normally.

Satchi-Fainaro, Folkman, and their colleagues describe the success in the March issue of Nature Medicine. While waiting for publication of the report, the team tried jumbo TNP-470 in other cancers, including spreading lung tumors in mice. It works well. "Frankly, it was a big surprise; we didn't expect the results to be so good," Folkman says.

"The conjugated drug molecules are too big to seep from normal blood vessels," Satchi-Fainaro explains. But they easily dribble out of leaky new blood vessels and into the tumors. "Once inside the tumors, the copolymer [added baggage] is cleaved chemically, and the TNP-470 can do its work. It stays longer in the tumor than the free molecule, so it's more effective."

Will they now try jumbo 470 in humans? "Absolutely," Folkman answers quickly. "Those who did the human trials with the free TNP-470 are eager to try the conjugated drug." These include cancer researchers at Dana-Farber Cancer Institute in Boston, a Harvard teaching hospital two blocks from Folkman's lab, and the M.D. Anderson Cancer Center in Houston.

That doesn't mean that it will soon be available to patients. "We have to start the testing all over again," Folkman points out. First there will be safety tests, then efficacy tests; small groups of patients, then larger groups. "It'll be several years before we can get FDA (Food and Drug Administration) approval." He says that's "frustrating," but he has his game face on.

Folkman sees jumbo TNP-470 being used together with other drugs. One example is Avastin, another blood-vessel wrecker based on his research that was approved Feb. 26 by the FDA. At Dana-Farber Cancer Institute, Avastin, combined with chemotherapy, is being tested on runaway breast cancer. Chemical therapy has tough side effects, so doctors give patients a chance to rest between doses. But blood vessels grow back during such intervals, making it more difficult to stop the spreading cancer. Now they use Avastin every day to choke and starve tumor cells.

Folkman pushes across the table a list of 17 different human tumors that respond to free TNP-470. Another list shows that the drug halts the spreading of five different lung and liver cancers. "That's amazing," he comments. "We expect the conjugated drug will perform better in these and other cancers."







Copyright 2007 by the President and Fellows of Harvard College