Folkman Looks Ahead
On the 10th floor of Boston's Children's Hospital, Dr. Judah Folkman--a gentle presence with a racing mind--sits down to talk. He offers coffee and cookies. He teaches, he questions, he wonders. He plunges back to the past, hurtles ahead to the future and then, bounding through his lab in his scientist's white coat, he marvels at the present. "Look at this," he says, peering at a cylinder filled with sloshing red liquid. "These are human tumor cells." Tiny white dots, like grains of sand--they are the vicious beasts that Folkman, 68, has spent a lifetime trying to tame. And not, he insists, without the help of others. Walking past lab tables cluttered with flasks and tubes, he greets his collaborators, boasting about their discoveries. "I'm conducting an orchestra here," he says. "I'm listening to the music."
And the tempo is picking up. Angiogenesis, Folkman's once derided theory that tumors grow by recruiting blood vessels for nourishment, is now widely accepted as a promising avenue in cancer treatment--and it is finally moving from experiments in mice to testing in humans. At least 20 drugs called angiogenesis inhibitors are now in clinical trials, including angiostatin and endostatin, the compounds isolated by Dr. Michael O'Reilly in Folkman's lab. Today, three years after those molecules were trumpeted on the front page of The New York Times--igniting first a media frenzy amid hopes for a cancer cure and then a backlash casting doubt on his results--the spotlight is once again on Folkman. A new book, "Dr. Folkman's War," is just hitting stores and, later this month, public television's "Nova" will air "Cancer Warrior," chronicling Folkman's pioneering work in the field.
The scientific community, meanwhile, is watching for data. The angiostatin trials, taking place at Thomas Jefferson University Hospital in Philadelphia, are still getting underway. But endostatin, under study at the Dana-Farber Cancer Institute in Boston, the M.D. Anderson in Houston and the University of Wisconsin in Madison, is already showing precisely what scientists had hoped for in phase-one safety testing: while it is far too soon to judge its effectiveness against cancer, it causes virtually no side effects. Although patients in these early trials are exceedingly sick and most saw their cancer continue to grow, there were some very preliminary positive signs: tumors stabilized or even regressed partially in several patients. And sophisticated imaging showed that as doses of endostatin increased, blood flow to tumors decreased in some patients--the goal of angiogenesis inhibitors. There is still healthy skepticism about whether one drug alone can shut down blood-vessel growth. And there is plenty to learn as trials continue. What is an effective dose? When in treatment should endostatin be given? Will a 24-hour continuous infusion of the drug, now being tested in patients, improve response and survival? "I think proof of concept is there," says M.D. Anderson's Dr. Roy Herbst, "but we still need to do a lot of work to eke out exactly how to use them."
Even people like Duane Gay, one of the first humans to be treated with endostatin, knows that the drug may not save him. Three years ago, on his first wedding anniversary, Gay, 44, learned that the connective-tissue cancer he'd kept at bay since 1991 had come roaring back. Endostatin, which he was given after traditional therapies failed, didn't eradicate the disease: a tumor in his rib grew by more than half. But masses in his liver, lungs and kidney stabilized, giving him hope--and boundless enthusiasm for the potential of anti-angiogenesis therapy. "I went in hoping that it would save my life, but I also feel privileged that I could help advance the science." Now, Gay and his wife are "praying for the scientists," he says. "And at the top of the list is Dr. Judah Folkman."
Folkman, the son of a rabbi--who told him on his bar mitzvah day, "Be a credit to your people"--is committed to answering those prayers. It hasn't been easy. He battled skeptics decades ago and he's battled them since by simply plowing ahead with his research. Today, as scientists and biotech companies pour time and money into developing angiogenesis drugs, there is plenty of enthusiasm for the field. Folkman, meantime, is focused on results. He is encouraged by success over the past decade treating children with life-threatening hemangiomas--masses of blood capillaries--with interferon-alpha, an older drug that has anti-angiogenic properties. As he projects before and after photos of tiny patients on the wall--the baby in a checked shirt, the girl in a red-flowered dress--Folkman maintains his quiet calm. But joy is all over the place. "Look," he says, "at what we've learned."
As trials continue, scientists will learn more about how best to use the new drugs. In combination with chemotherapy and radiation (which go after tumor cells), a strike against the enemy could be much more powerful--blasting not just troop headquarters, but the supply lines, too. One day, doctors might be able to take a tumor's thumbprint by testing urine, blood or tissue for the angiogenesis proteins that are busy recruiting blood vessels--then prescribe a cocktail of inhibitors that would stop them in their tracks. The drugs might even be given long term to prevent tumors from surging back--a still unsolved and endlessly frustrating challenge in treatment. "If we can't cure cancer, I would be very willing to turn it into a chronic disease," says Dr. James Pluda of the National Cancer Institute. "These drugs have that kind of potential."
And there is potential, too, for angiogenesis drugs to play a role in a host of other illnesses, including heart disease. Near the elevators leading out of his lab, Folkman lingers to talk, never tiring of his subject. "You have to think ahead," he says. "Science goes where you imagine it." We can only imagine it will get better and better.
