Folkman Finds Anti-Cancer Substance

Researchers at Boston Children's Hospital have discovered a naturally occurring protein fragment which has been shown to inhibit tumor growth in mice, the third isolated at the hospital's labs.

The Medical School's Andrus Professor of Pediatric Surgery M. Judah Folkman announced last Friday that tests at his lab at the Children's Hospital had confirmed the effectiveness in mice of the protein fragment, called antiangiogenic antithrombin (aaAT), in suppressing the formation of blood vessels that feed tumor growth.

This discovery comes less than two years after Folkman published his lab's detection of the second of two protein fragments thought to suppress tumor growth. The three fragments have only been tested in animals, and it will be impossible to judge the potential of these substances in fighting human cancers until extensive clinical trials are held, at least.

In a 1997 article in the journal Cell, researchers in Folkman's lab, including Folkman and angiostatin discoverer Michael S. O'Reilly, wrote that their findings and experimental data "suggest a theme of fragments of proteins as angiogenesis [blood vessel growth] inhibitors."

As explained in an article in the Sept. 17 issue of the journal Science, the human body contains numerous proteins which limit blood vessel growth under normal conditions such as menstruation and wound healing.

Now researchers speculate that these proteins may also inhibit cancer growth.

The aaAT fragment was first discovered in human lung cancer cells by O'Reilly, a clinical fellow at the Children's Hospital.

The protein's sequence was first analyzed at the Harvard Microchemistry Facility. William S. Lane, director of the facility, said that although his lab's high-tech equipment aided the discovery, it is the Folkman lab that should be congratulated.

"We determined the peptide sequence," Lane said. "But kudos to Folkman and O'Reilly for isolating the protein," he stressed.

Two other scientists in Folkman's lab, Oliver Kisker and Steven Pirie-Shepherd, later confirmed O'Reilly's finding when they saw the same protein being produced by human pancreatic cancer cells.

By implanting human tumors into mice and comparing tumor growth, scientists can try to identify which types of human tumors could possibly be used in future to inhibit cancers, according to the Science article.

Folkman's lab has previously reported successful experiments using the anti-angiogenic proteins endostatin and angiostatin on tumors in mice. In those experiments, the substances were shown to cause tumors in mice to regress to microscopic size.

These results have been duplicated by scientists at the National Cancer Institute, according to its recent press release.

Researchers at Bristol Myers Squibb and other biotechnology companies, however, say they are unable to reproduce the results, stirring some controversy over the validity of Folkman's methodology.

Mallinckrodt Professor of Chemistry George M. Whitesides '60 suggested that disparity between labs' results may stem from the different ways they are trying to relate the vascular system's growth to tumor growth.

"Folkman has his approaches to this problem; other research groups and companies have other approaches," he said. "But the point is that the concept of inhibition of angiogenesis is a fundamentally very important one, both because it seems to me very likely that it will work, at least in some

cases, and because it has stimulated new ways of thinking about the very difficult problem of treating cancer."

Whitesides explained that Folkman's research uses a methodology of attacking "normal" tissues that support a cancer, such as vascular tissue, rather than targeting the cancer itself.

"Folkman's work has produced a shift in the way that the biomedical community is thinking about

treatment of cancer," he said.

Traditional cancer therapies--including surgery, radiation and chemotherapy--overlook the fact that cancer, a derangement of the genome, has a strong tendency to mutate and become insensitive to certain treatment agents.

Whitesides added that those traditional treatments may not help in those cases where the cancer spreads beyond the treated, or treatable, areas. Traditional cancer therapies are also notoriously hard on the patient as both malignant and normal tissues are susceptible to toxic agents.

According to officials at the Children's Hospital, the first phase of clinical trials in humans with endostatin will begin in Boston in late September. Angiostatin is expected to enter Phase I clinical trials next year.

Lane, sounding a cautionary note about the expectations for a human cancer therapy that Folkman's work has already raised, articulated the goal of clinical trials.

"As in much of science, the promise comes in things that the public might not see, not in successes or failures, but in how this leads to further discovery," he said.