Of Mice And Men And Cancer

Chemicals that promise to choke off the blood supply to tumors are now in human trials

A year after a frenzy of media hype seemed to promise--and then to rule out--a spectacular cancer cure, progress is quietly being made in the search for treatments that starve tumors by cutting off their blood supply. Some 20 compounds that halt the growth of new blood vessels, a process called angiogenesis, are now in human trials, and at this spring's cancer meetings, researchers are reporting promising results.

Claims that angiogenesis blockers could be a magic bullet that would cure cancer swept the world last May after a front-page story in The New York Times reported on two potent compounds first publicized in 1997. Angiostatin and endostatin, discovered in the lab of Dr. M. Judah Folkman of Children's Hospital in Boston and licensed to EntreMed Inc. of Rockville, Md., stopped malignant tumors in their tracks--in mice. Talk of a human cure, however, was wildly premature.

Since then, angiostatin and endostatin have been on a roller-coaster ride. A research team at the National Cancer Institute (NCI) reported last November that it could not duplicate Folkman's success in mice. Then, in February, it reported it had. The same month, Bristol-Myers Squibb Co., which is funding part of EntreMed's research, dropped its support of angiostatin, saying the drug was too difficult to manufacture. Endostatin has proven more successful: At the mid-April annual meeting of the American Association for Cancer Research (AACR) in Philadelphia, EntreMed said that it has produced enough of the drug to move ahead with human trials later this year.

The better news for cancer patients, however, is that angiostatin and endostatin are only one piece of what is now one of the most active areas of cancer research. There are dozens of angiogenesis inhibitors in development, all with different mechanisms of action. Several broad-acting agents are in the final stage of clinical trials, while more focused drugs, aimed at blocking one or more of the 15 chemical signals known to activate blood-vessel growth, are in different stages of human testing.

Sugen Inc. of South San Francisco, Calif., for example, is planning advanced clinical trials for SU5416, which blocks vascular endothelial growth factor (VEGF), a key chemical for triggering blood-vessel growth common to some 80% of solid tumors. Anti-VEGF "is one of the more important angiogenesis inhibitors" because it has such a broad action, says Isaiah J. Fidler, a leading cancer researcher at the University of Texas-M.D. Anderson Cancer Center in Houston. Zeneca, Genentech, and Novartis are also working on VEGF blockers.

EARLY PEEK. Sugen plans to announce results in May of an early-stage human trial of its drug against Kaposi's sarcoma, an AIDS-related cancer. In an early peek at the results at the AACR meeting, Jerry McMahon, vice-president for drug discovery, reported that there was "a very nice response." The drug, he said, is fast-acting and had a long-lasting effect.

Folkman, who consigned all rights to angiostatin and endostatin to Children's Hospital, is heartened by the competition to his lab's discoveries, in part because it proves the renowned scientist's own theories. "The point is that the principle of angiogenesis has been well-established," he says. "The problem now is how to make the drug." To Folkman, the good news is that there are plenty of other candidates as intriguing as the ones discovered in his own lab.

Indeed, Folkman's discovery has led to a sea change in cancer research. Scientists increasingly try to block a cancer's deadly effects on the body, rather than kill the tumor itself. "Let's face it, the majority of cancer patients die from metastases [spreading tumors], not primary tumors," says Anderson's Fidler--and the higher the density of blood vessels around a tumor, the better its ability to spread. That's because tumors can use the blood vessels as conduits for their malignant cells. Researchers caution that anti-angiogenesis agents are unlikely to eradicate the initial tumor, but they are hopeful that it can be stopped in its tracks.

It is this hope that has sent molecular biologists on a painstaking search for the molecular triggers that cancerous cells use to spur blood-vessel growth--a complex dance of chemical signals between tumor cells and the endothelial cells that line blood vessels. "There are many different steps and places and ways one can interfere with the system," says James Pluda, the NCI's senior clinical investigator overseeing angiogenesis inhibitors. "The compounds now in trials represent a wide variety of mechanisms, but there could be others."

NATURAL BRAKES. Folkman first theorized in the early 1970s that tumors cannot grow without inducing the growth of new blood vessels. But it is only in the past five years that scientists have isolated the cellular mechanisms that control the process. Angiostatin and endostatin stirred up particular excitement because they are the body's own natural brakes on blood-vessel formation. But because these proteins are large molecules, they are hard to synthesize.

Folkman is intrigued by a new discovery that may get around that problem. Researchers at Duke University have identified the receptor on the endothelial cells to which angiostatin binds. A small molecule could be synthesized, says Folkman, that would be just as accurate in honing in on the receptor.

After last year's white-hot focus on anti-angiogenesis, researchers in the field are extremely cautious about promising much, if anything. It could still be several years before a drug wins approval, and even then researchers say the treatments will likely be given in combination with chemotherapy. So no one will use the loaded word "cure"--but cautious optimism might be appropriate.

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