HARVARD GAZETTE ARCHIVES
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.
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.
"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."