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Crazy ideas

Three researchers who took on the unconventional and the infamous

Two years into his ophthalmology residency at Massachusetts Eye and Ear Infirmary, Robert D'Amato, MD, PhD, attended a lecture by Children's Hospital Boston researcher Judah Folkman, MD. It was 1991, and Folkman's vision of treating blinding eye diseases by blocking blood-vessel growth, or angiogenesis, so enthralled D'Amato that he immediately wrote to Folkman about joining his lab.

There was no reply. "Dr. Folkman had a stack of hundreds of CVs," D'Amato says. "He was always working his way through them." Finally, a former mentor helped arrange a meeting.

The most important project in the lab, Folkman said, was to find an oral angiogenesis inhibitor. By blocking blood-vessel growth with an oral drug, cancer patients could be cared for as outpatients, and others with chronic diseases reliant on angiogenesis, like macular degeneration, would also benefit. D'Amato was concerned about side effects, but Folkman said there wouldn't be any. D'Amato was hooked.

But Folkman could only fund him for six months, so D'Amato laid out the project while still completing his residency. His pharmacology training told him that blocking blood-vessel growth would have side effects somewhere in the body. By identifying drugs with such side effects, he might find an angiogenesis inhibitor. He visualized his own body, from head to toe, but couldn't think of anything that anti-angiogenic drugs might disrupt.

Then it hit him: What about a woman's body? This gave two obvious possibilities: menstruation and pregnancy. In a search for drugs with reported effects on these functions, one drug stood out: the notorious thalidomide, pulled from the market because of horrific birth defects. Could the stunted limbs of "thalidomide babies" have been caused by inhibition of angiogenesis?

D'Amato arrived in Folkman's lab, his six-month clock ticking, ready to begin testing thalidomide. "People thought I was crazy," he remembers. "They said no one would ever take that drug again." But Folkman encouraged D'Amato to go ahead with it. Thirty years earlier, Folkman himself had faced colleagues' disbelief when he proposed that a cancer could be stopped by halting its blood supply.

D'Amato's experiments led to the discovery of one of the most effective angiogenesis inhibitors available to patients. Thalidomide and its close relative Revlimid are now first-line, FDA-approved therapies for multiple myeloma and are in clinical trials for several other cancers.

The next generation
In early 1998, Michael Rogers was working toward his PhD at the Mayo Clinic when he, too, attended a lecture by Folkman. Like D'Amato, he was captivated, inquired about joining the lab, and heard nothing back. But D'Amato himself was looking for a research fellow to identify genes that make angiogenesis more likely to switch on, thus encouraging tumors to grow. In Folkman's backlog of CVs, he found Rogers.

D'Amato encouraged Rogers to test his own ideas in his spare time. Riding the train from work one day, Rogers met a Harvard colleague, Ken Christensen, PhD, and learned he was working with another infamous agent: anthrax.

Christensen mentioned that anthrax has a harmless fragment called anthrax protective antigen (PA) that binds to endothelial cells, which line the walls of blood vessels, using a special receptor called capillary morphogenesis gene 2 (CMG2) protein. Rogers knew CMG2 well—he had identified its gene as a potential regulator of genetic differences in angiogenesis—and he suspected that CMG2 aided the movement of endothelial cells, spurring blood vessel growth. Would tying up CMG2 with anthrax PA prevent this movement? And could this stop angiogenesis?

Meeting Christensen in front of Harvard Medical School, Rogers procured a sample of anthrax PA. Although anthrax PA alone is harmless, it was potentially more controversial than thalidomide. "When we did the first experiments, we didn't talk about what we were working with," says Rogers.

Anthrax PA did inhibit angiogenesis, but it was taken up too rapidly by endothelial cells to make a good drug candidate. Experiments with related compounds followed, and in a paper in Cancer Research last October, Rogers and D'Amato showed one of these to powerfully inhibit tumor growth in animals. Rogers and D'Amato feel a large debt to Folkman. "Dr. Folkman created an environment that encourages people to have big and sometimes crazy ideas," says Rogers. "He allowed us to rekindle the excitement that brought us to science in the first place."