By David N. Leff

Chop 'em! Burn 'em! Poison 'em!

As the U.S. war on cancer (declared in 1970), winds up its third decade, these three modalities — surgery, radiation, chemotherapy — remain the sole conventional weapons in the antimalignancy arsenal. Immunotherapy and gene therapy are still under development.

Solid tumors fight back with weapons of their own, of which the most devastating is drug resistance to chemotherapy. Chemotherapy is the oncologist's last, best hope of counter-attacking metastases, once surgery has removed the bulk of a primary tumor and radiation has attempted to clean out residual neoplastic cells.

"Tumor cells have a high mutation rate," observed oncologist Michael O'Reilly. "One of a tumor cell's hallmarks is that it mutates; its cells are genetically unstable. So when you give chemotherapy, although you may eradicate a majority of those cells, you risk leaving behind a small but growing population of cancer cells that are drug resistant."

Just as a pathogenic virus hijacks its victim's own cells to support viral replication and infectivity, so a solid tumor cell subverts its host into supplying the nutrients and oxygen that foster the malignancy's out-of-control growth. What it does is compel the cancer patient's blood vessels to create and expand a network of capillaries, veinlets and arterioles to feed its growth habit. That is, the wild-card tumor cell forces its victim to commit angiogenesis.

O'Reilly is a clinical and research oncologist in the laboratory of surgeon Judah Folkman, at Children's Hospital, in Boston. For the better part of three decades, Folkman has been developing strategies and tactics for shutting off the body's donation of lifeblood to the tumor bent on ending that life. Many of his experimental treatments are in clinical trials at cancer centers through the U.S. and abroad.

Folkman's latest end-run around the tumor's blood-sucking assault enlists the blood vessels' own endothelia. These are the flat, smooth, seamless cells that line the inner walls of arteries, veins and capillaries.

Endothelial cells, O'Reilly pointed out, even those exported into a tumor's spreading network of blood vessels, are normal, nonmalignant. "So," he pointed out, "if we could develop ways to target endothelial cells in the tumor, and inhibit them, one would expect that there won't be any drug-resistant endothelial cells.

"Physiologically," he explained, "they would act something like gate-keepers, to prevent the disordered growth of blood vessels."

O'Reilly and Folkman are co-senior authors of an article in the current issue of Nature, dated Nov. 27, 1997, which bears the title: "Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance."

What Helps Strawberry Marks Fade

That therapy exploits a natural substance, which turns off the growth of endothelial cells. O'Reilly discovered that protein in a mouse with hemangioendothelioma — a blood-vessel tumor. Its human version is the familiar "strawberry mark," a cluster of bright red capillaries just under the skin of newborn babies. It usually disappears in the first months or years of life.

Presumably, O'Reilly reasoned, something inhibits these angiomas. "We ended up purifying this inhibitor from those mouse tumor cells," he told BioWorld Today, "and named it "endostatin." It resembled an earlier endothelial-cell inhibitor O'Reilly had found in 1994 and called "angiostatin."

This year, he and his co-authors synthesized enough recombinant endostatin to test its effectiveness in tumor-bearing mice. First they inoculated cohorts of these rodents with one of three murine solid tumors — lung carcinoma, fibrosarcoma and melanoma — then dosed them with endostatin.

After the tumors had grown under the skins of the animals to a respectable size — about three percent of their body weight — the team infused them with endostatin until the tumors dwindled. When they stopped the inhibitor treatment, the cancers grew back. They repeated this on-again, off-again growth-inhibition regimen for up to six cycles, about 140 days. At that point, the tumors were microscopically small and had given up on re-growing. In effect, they finally failed to develop resistance to the endostatin chemotherapy.

Endostatin Beats Tumors Into Submission

"The surprising finding with this Nature paper," O'Reilly told BioWorld Today, "was that if we treat the mice up and down with enough angiogenesis inhibitors, for some reason they don't come back. Instead, they enter what we're calling a self-sustained dormancy, where even off therapy the tumors remain microscopic."

He continued: "We think this is the first model for studying why, say, in someone who has a cancer treated, and then is apparently disease-free for a number of years, but then for one reason or another the tumor comes back."

O'Reilly pointed out that "the dormant state is certainly something that our mice can live with. That is, the tumor cells are there but they're not causing any harm. We've taken the malignancy out of the cell, so to speak. They're still proliferating rapidly, but they're dying much more rapidly as well."

O'Reilly doesn't see endostatin and angiostatin as "necessarily going to compete with other cancer therapies. We're hoping we can integrate them with existing modalities — conventional chemotherapy, radiation and surgery. Perhaps that could eradicate what's left of the tumors.

"Since cancer is such a multifaceted disease," he went on, "we think that, using angiogenesis inhibitors, we might be able to maximize the benefit of some of these standard therapies. Other strategies would be with some of the newer techniques, including immunotherapy and gene therapy, telomerase therapy and what have you. We think an angiogenesis inhibitor might make tumors an ideal target for some of those newer kinds of treatment — and minimize their toxicities."

Children's Hospital has licensed angiostatin to EntreMed Inc., of Rockville, Md. That company's president, chairman and CEO is neuropharmacologist John Holaday.

"We have had for two years a partnership on angiostatin with Bristol-Myers Squibb Co., of New York," Holaday told BioWorld Today, "Right now, we're scaling up in anticipation of Phase I toxicity studies, going into clinical trials, in the next year or two.

"We have not licensed or sublicensed endostatin, except that we have a partnership with the National Cancer Institute. Working with them, we are now scaling up manufacture of endostatin, and perhaps that's come along so fast that we're almost catching up with angiostatin in terms of its clinical-trial timetable.

"It's such a revolutionary concept," Holaday concluded, "that we're very fortunate to be the vehicle through which Judah Folkman and Children's Hospital will get these products out to man." *

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