By David N. Leff

An offhand remark by DNA Nobel laureate James Watson at an informal dinner party last spring touched off a media feeding frenzy (including cover-story coverage in all three newsweeklies), a surge in the stock of a small biotech company, high hopes among the cancer-anxious public, and subsequent retractions and recriminations.

On the front page of its Sunday, May 3, 1998, edition, the New York Times quoted Watson as having said, "Judah is going to cure cancer in two years." Watson was referring to surgeon Judah Folkman of anti-angiogenesis reknown, who had tested two blood-vessel-blocking compounds, angiostatin and endostatin, in mice, with promising preliminary results against malignancies. The experimental treatment starved tumors growing on the animals of blood-borne oxygen and nutrients.

Unhappily, this blockbuster report in the Times had a couple of flaws:

* It was old news. Folkman's tumor-blocking experiment had been published five months earlier, in the Nov. 27, 1997, issue of Nature. (See BioWorld Today, Dec. 2, 1997, p. 1.)

* While cancer patients and their relatives, clamored for Folkman's two new drugs, the fact is that barely enough of the proteins is being produced to fuel ongoing and future mouse trials, let alone imminent human studies.

In the wake of the story in the nation's leading paper, stock in EntreMed Inc. — which had licensed from Harvard-affiliated Children's Hospital, in Boston, rights to the two anti-angiogenic proteins featured — soared. On Monday, May 4, the Rockville, Md., firm's shares (NASDAQ:ENMD) opened at $85, a gain of about 700 percent. EntreMed would end that heady Monday at $51.813 — a quadruple bounce. But the firm's shares have since settled into the $24 range. (See BioWorld Today, May 5, 1998, p. 1.)

All of the above is prologue to a paper in the current issue of Science, dated Oct. 16, 1998, titled "Increased vascularization in mice overexpressing angiopoietin-1."

Its principal author is George Yancopoulos, senior vice president of research and chief scientific officer at Regeneron Pharmaceuticals Inc, in Tarrytown, N.Y.

Yancopoulos told BioWorld Today, "Folkman is primarily interested in anti-angiogenesis, not necessarily in growing blood vessels. As we report in this week's Science, our angiopoietin-1 has to do with growing vessels — the flip side of blocking them."

The inner lining of arteries, veins and capillaries consists of endothelial cells. Embryonic development of this blood-distributing network begins with vasculogenesis, during which those endothelial cells differentiate, proliferate and merge to form the primitive blood-vessel system. This initial stage relies on vascular endothelial growth factor (VEGF).

Then angiogenesis takes over, to remodel that rough-draft network, through sprouting, branching, pruning and differential growth of those vessels into their final form. This stage calls for a different growth factor, angiopoietin-1, which Regeneron discovered and cloned some two years ago, Yancopoulos recalled.

Two Contrarian Foes: Tumors, Ischemia

Just as anti-angiogenesis targets tumor growth, angiogenesis takes aim at ischemia — the cutting off of blood supply. To counter myocardial ischemia, half a million heart bypass operations a year take place in the U.S., plus 400,000 angioplasties — reaming open blocked arteries. Surgeons have begun trying gene therapy as an alternative, injecting the gene for VEGF directly into cardiac tissue. (See BioWorld Today, Jan. 7, 1998, p. 1.)

In their first in vivo trial of angiopoietin-1, Yancopoulos and his co-authors elected to insert the gene for their growth factor under the skins of mice. "We were interested to prove the principle that angiopoietin-1 could promote blood-vessel growth. So when we looked at ways to do it, we said, 'Well, one of the best ways would be to pick a specific tissue promoter and use it to draw the angiopoietin into a tissue of therapeutic interest.' " Obviously, he added, "one of the places where ischemia can be very troublesome is wound-healing in the skin. That's also a good structure for evaluating the vasculature; it's very accessible."

Whereupon, the team created transgenic mice that overexpressed the protein in their skins. The results of their experiments were overtly visible as an inherent equivalent of color-coding. "We literally got red mice," Yancopoulos said. "It's the most striking phenotype that we've seen when we try to grow blood vessels." The animals overexpressed the growth factor 12-fold, and got redder and redder as they grew older.

As for clinical implications, Yancopoulos demurred. "We don't want to jump to any conclusions, which I think is one of the problems in this field. There are obvious therapeutic indications that one has to consider, and those are the directions in which Regeneron is considering going. That is, promoting blood-vessel growth against the ischemic-type situation.

"In cardiac tissue," he said, "you have poor blood flow for a variety of reasons. In many patients, for example, their problem is not necessarily amenable to surgical approaches, like bypass, because they have small-vessel disease. So you need to figure out a way to grow better small vessels." He said diabetics in particular have a lot of problems with peripheral tissue, "such as skeletal muscle and surface tissue sores — decubitus ulcers that don't heal. These often lead to forced limb amputation." These sorts of indications, he said, "are clinical settings in which one would want to grow blood vessels."

But There's A Flip Side To Angiopoietin

"The beauty of the angiopoietin system," Yancopoulos said, "is that it's the only growth factor system in the body shown to have naturally occurring agonists — namely, angiopoetin-1, and antagonists — angiopoetin-2, which we reported on in Science about a year ago. In this case, that naturally occurring antagonist — angiopoetin-2 — actually blocks the receptor that is activated by angiopoetin-1. And when we overexpressed it transgenically, we completely blocked or disrupted blood vessel development in the mouse embryo. So the flip side we can consider is using it to slow or block blood vessel growth, in tumor settings, for example."

Diabetics, he noted, "also face blindness from overgrowth of retinal blood vessels." *

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