Neuroblastoma is a none-too-rare malignancy of infants and toddlers.

"It's a solid tumor that afflicts 650 cases in the U.S. every year," observed pediatric oncologist Darrell Yamashiro, at Columbia University College of Physicians & Surgeons in New York. "The majority of neuroblastomas, two out of three patients diagnosed," he added, "are under 5 years of age, with the average about 2 years.

"When a neuroblastoma metastasizes, as it starts to grow, only one in three patients will probably be cured. That is why," he commented, "we were interested in this cancer."

Yamashiro's interest took the form of a novel anticancer agent, as reported in the current Proceedings of the National Academy of Sciences (PNAS), an "early edition" released online Aug. 13, 2002. He is senior author of that paper, which bears the title: "Potent VEGF blockade causes regression of coopted [blood] vessels in a model of neuroblastoma."

A companion article in the same PNAS issue is titled: "VEGF-Trap: A VEGF [vascular endothelial growth factor] blocker with potent antitumor effects." Its senior author is biotechnologist George Yancopoulos, chief scientific officer at Regeneron Pharmaceuticals Inc., of Tarrytown, N.Y., and president of Regeneron Research Laboratories. His co-senior author is Regeneron's John Rudge.

Commenting on his paper in PNAS, Yancopoulos told BioWorld Today, "The first thing is that there's been a lot of excitement in the field of angiogenesis over the last five years or so. But now there's also been a rebound phenomenon, with increasing skepticism and so forth as to whether some of the claims and potentials will be appreciated in human clinical trials. One of these realizations," he continued, "is that although there are probably more than 50 anti-angiogenic compounds going into the clinic over the last few years, it's become realized that of all these, the only ones that seem to be hitting a validated pathway are those hitting the VEGF pathway. It seems that by far the most exciting - and the one that most likely fulfills the potential of all these agents - is Genentech's humanized antibody against VEGF.

Regeneron Takes On Genentech's Antibody

"So my whole strategy," Yancopoulos continued, "is that Regeneron wants to come up with perhaps a better VEGF blocker, and then move forward with that. Our paper reports what is perhaps the most potent blocker the VEGF pathway has ever described - VEGF-Trap. Based on that," he went on, "one would expect it might have a dramatic effect in animal studies. Indeed, that's what these two papers also showed. Not only did we come up with perhaps a better blocker biochemically, but it seems to achieve this promise in Columbia's animal models. As the figures in our papers show, VEGF-Trap can completely block - literally leave no blood vessels - in the Trap-treated preclinical tumor mouse models. And in side-by-side comparison, it seems to perform significantly better than other agents out there."

VEGF-Trap is a composite decoy receptor based on two VEGF receptors fused to a segment of immunoglobulin G. The preclinical studies compared VEGF-Trap to three current approaches to blocking angiogenesis: One is a monoclonal antibody that binds and blocks VEGF. A second, an RNA-based molecule also binds and blocks VEGF - the vascular endothelial growth factor. The third is an antibody that inhibits the VEGF receptor.

"As our study described," Yancopoulos went on, "we showed how the VEGF-Trap agent could be 100- to 1,000-fold more potent than any pre-existing angiogenesis blockers. What the Columbia University group did was take VEGF-Trap to the next level of performance. They showed that besides completely inhibiting blood vessel spread, they actually restricted tumors to a type of malignant growth known as cooption. Furthermore, they could even see tumor regression in some of those coopted vessels."

Yamashiro told BioWorld Today, "We found first that when a neuroblastoma tumor is growing in a kidney, blood vessels in the host's body - in our case, mice - take over existing growth. However, VEGF-Trap at high doses inhibits cooption, with the implication that cancer therapy can prevent cooption of all angiogenic vessels. Cooption," he explained, "involves a tumor taking over existing blood vessels, as in the kidney where most neuroblastomas grow." The tumor tissue surrounds the mouse's normal blood vessels in the kidney.

Yancopoulos picked up on cooption with a (literally) homely metaphor: "Imagine if you were a thirsty organism next to a house with pipes in it. There were two ways you could get access to the water in that plumbing. One, create a new connection tapping into those pipes. That's new angiogenesis. But let's say you had an anti-angiogenic agent that completely blocked the piping. If you were very thirsty, you could start destroying the house, and just take over the pipes. That's exactly what tumors do. They can invade normal tissues, leave the vessels intact - and divert them to their own nefarious uses."

VEGF-Trap-Treated Mice Hit 81 Percent

"Yamashiro's Columbia group," Yancopoulos continued, "put tumors into their normal location. And the tumor destroyed the normal kidney tissue. In an amazing demonstration, what they actually showed is that it left the renal blood vessels intact, and just tapped into them. So the only tissues that it saved were the blood vessels, which the tumor started using for its own evil purposes. That's cooption.

"So the way our two PNAS stories break down," he went on, "they show that when we force tumors to grow in the absence of VEGF, instead of growing their own vessels, they take over parasitically their host vessels. Then if you have strong VEGF blockade ongoing, those coopted vessels themselves can undergo tumor regression, with the ultimate hope that if you do this long enough, you can get shrinkage of existing tumors."

Columbia's in vivo experiment with VEGF-Trap began by inoculating neuroblastoma cells into the kidney-adjacent adrenal gland. "We let the tumors grow for one week," Yamashiro recounted, "then treated them with VEGF-Trap twice a week, via intraperitoneal injection. Four to six weeks later, we sacrificed the mice and measured their tumor angiogenesis. We observed a high range of efficacy, with high-dose VEGF-Trap abolishing the tumors, and causing the greatest inhibition of cancer growth," he concluded, "81 percent, compared with control animals."

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