CANCER `CURE' WILL BE TESTED; DRUG WORKS ON MICE, BUT HOW ABOUT PEOPLE?

Byline: John Crewdson Chicago Tribune

When Moses Judah Folkman emerges from his Harvard laboratory for a rare public appearance at the annual meeting of the American Association for Cancer Research here today, the scientific world will be watching - and waiting.

By late summer, barring unforeseen circumstances, a tiny group of cancer patients in Wisconsin and a slightly larger group in Texas will become the first humans treated with a drug discovered by Folkman that causes cancer to vanish in mice.

``We're in a sensitive period,'' said Folkman, who has been awaiting this moment for many years. ``Because now we're within the year of starting. It's no longer two or three years off. There's been a ton of work and effort. We're working around the clock. So - we'll see.''

Folkman's drug is a protein he calls endostatin, the product of a single-minded, three-decade pursuit of one scientist's conviction that the way to cure malignant tumors is to cut off their blood supply.

Despite its elegant simplicity, until recent years Folkman's theory was more than a little controversial. ``We could not always convince everybody,'' he said, ``but if you know enough yourself, you can keep going.''

Colleagues and competitors alike now say they are convinced that Folkman has proven his principle, at least in mice: Thwarting angiogenesis, as the process of forming new blood vessels is known, effectively starves many tumors of the nutrients they need to grow and spread.

Once the object of scientific derision, angiogenesis has become the most talked-about topic in cancer research.

Until recently, only Folkman had published data showing the dramatic shrinking effect of endostatin, and another protein called angiostatin, on tumors in mice. Angiostatin and endostatin are fragments of two larger proteins, collagen and plasminogen, that occur naturally in the body.

In Folkman's lab, continuous treatment with angiostatin makes mouse tumors shrink in size, although the tumors return when the treatment stops. A half-dozen cycles of the more powerful endostatin shrinks mouse tumors to barely visible nodules that remain dormant even after mice are no longer given the drug. When the two drugs were used together, a single three-week treatment made tumors disappear.

While other cancer drugs have performed better in the laboratory than in humans, no one had ever achieved Folkman's results in mice - results that other researchers describe with superlatives like ``unprecedented,'' ``stunning'' and ``startling.''

Similar results

Over the last year, several other laboratories, at Harvard and elsewhere, have obtained similar data, some of which will be unveiled here this week. As a result, much more is now understood about how endostatin and angiostatin work, and about the process of angiogenesis in general.

Only last week, Folkman himself published new evidence - again from mice - suggesting that endostatin might protect against heart disease by controlling the blockage of coronary arteries.

The real focus of interest, however, is how Folkman's drugs will work in cancer patients. Although no one, including Folkman, expects to see the same dramatic results in humans that occur in mice, the managers of the upcoming trials describe themselves as cautiously optimistic. Folkman says he will be ``very surprised'' if endostatin fails to help people with cancer, at least to some degree.

Although the human trials cannot begin until they have been approved by the U.S. Food and Drug Administration, and until enough endostatin has been produced to treat the patients, the groundwork is rapidly being laid.

FDA approval is expected, considering that monkeys have received massive doses of endostatin with no adverse effects. Dr. James Thomas of the University of Wisconsin in Madison, where one of the two trials will take place, says the National Cancer Institute ``is telling us there will be enough endostatin to begin in four to six months, sometime between July and September.''

Production `on time'

A spokeswoman for Covance Biotechnology Services, which has a contract to produce a little more than two pounds of recombinant human endostatin at its facility in North Carolina's Research Triangle Park, says the process is ``on time and on schedule.'' Folkman has tested the Covance endostatin and pronounces it ``very good.''

Folkman became a reluctant worldwide media celebrity last May, when The New York Times quoted Dr. James Watson, co-discoverer of the DNA Double Helix, as predicting that Folkman would ``cure cancer in two years.'' Watson later said he could not recall having made such a prediction but called Folkman's work ``the most exciting cancer research of my lifetime.''

Folkman, whose research has focused on a particularly aggressive form of lung cancer in mice, says he has extended his endostatin experiments to mice with transplanted human prostate tumors.

``I'm doing it myself, with my assistant,'' he said. ``I inject them. I want to see every step. I want to see, does it hurt the skin? No. Does it make them shaky? No, they love it.

``And the untreated ones with the big tumors are losing weight, just like cancer patients. And the treated ones - tiny, tiny tumors and they're gaining weight. Very exciting, but it's just sort of muted excitement. Because we know about over-expectation.''