September 23, 1999
Harvard
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HARVARD GAZETTE ARCHIVES

New Anti-Cancer Drug Discovered

By William J. Cromie
Gazette Staff


Michael O'Reilly (left) and Judah Folkman have discovered three natural blood-clotting substances that shrink cancer tumors by cutting off their blood supply. Photo by Mary Lee.

A natural protein capable of shrinking tumors and blocking the spread of cancer has been discovered by Harvard Medical School researchers who already have found two promising anti-cancer drugs.

Known as aaAT, the protein is a fragment of antithrombin, which prevents blood clotting in the legs and elsewhere. The aaAT (anti-angiogenic antithrombin) blocks growth of human lung tumors implanted in mice. It was discovered by Michael O’Reilly, a research fellow working in the laboratory of Judah Folkman, Andrus Professor of Pediatric Surgery.

Two years ago, O’Reilly discovered ostatin, a powerful anti-tumor drug that is about to be tested in humans. "This new substance has the same potency," says Folkman, whose lab is located at Harvard-affiliated Children’s Hospital in Boston. "We hope to test aaAT in humans within the next few years."

Two other researchers in the same lab, Steven Pirie-Shepherd and Oliver Kisker, found that aaAT is also present in human pancreatic cancer cells. "We waited for confirmation of their results before we announced our own experiments," Folkman noted.

ostatin, aaAT, and a third drug, angiostatin, discovered in 1994, shrink tumors by preventing the growth of blood vessels that carry nutrients and oxygen to the cancers. "Finding that clotting pathways are involved in the regulation of angiogenesis (blood-vessel growth) gives us new insight," Folkman notes. "It means that the body is a storehouse of angiogenesis inhibitors. We have already begun looking for more of them."

The fact that such substances occur naturally in the body lessens or eliminates the risk that the drugs will have toxic side effects, a big plus for any cancer drug.

The discovery of how aaAT works in human lung cancers is described in the Sept. 17 issue of the journal Science. The discovery of the same protein in human pancreatic tumors will be published later.

Solving An Old Mystery

In finding aaAT, Folkman’s team solved an old mystery. For more than 30 years, researchers have known that if certain tumors grow on one side of an animal’s body, they often do not grow on the other side. No one could understand why.

O’Reilly began the experiments with test tubes full of millions of human cancer cells. He split those cells between different sides of the mice.

Large lung-cancer tumors grew on one side but those on the other side remained small. The researchers concluded that the large tumors stimulated growth of their own blood vessels, but at the same time they released an anti-angiogenesis inhibitor that prevented blood-vessel growth to the smaller tumors.

"Tumor growth is a balancing act," Folkman comments. "When inhibitors overwhelm factors that cause new blood vessels to grow, there will be no tumor growth. When growth factors get the upper hand, cancer grows and spreads."

The researchers extracted a protein from the mice that they suspected of inhibiting tumor growth, and O’Reilly carried samples in dry ice to Harvard’s Microchemistry Facility in Cambridge, Mass. Here, biochemists used sophisticated instruments to break down the protein, determine its makeup, and thus identify it.

"When we saw it was a fragment of antithrombin – a familiar protein – we got very excited," said William Lane, director of the Microchemistry Facility.

Children’s Hospital is collaborating with Genzyme Inc., a Cambridge biotechnology company, to make aaAT for ongoing experiments. EntreMed, a Maryland company, is licensed to develop ostatin. Upcoming tests of ostatin are slated to begin in a few weeks at Dana-Farber Cancer Institute in Boston; M.D. Anderson Cancer Center in Texas; and the University of Wisconsin.

Circulating in the blood, antithrombin can prevent clotting. When antithrombin encounters a tumor, cancer cells react by cleaving out the fragment called aaAT, which then blocks the formation of new blood vessels.

"It’s like having two jobs, one in the morning and one at night," Folkman comments. "The clotting function aids in wound healing, while inhibition of angiogenesis provides a potent anti-cancer drug."

 


Copyright 1999 President and Fellows of Harvard College