Farber's disease

Treatments based on Folkman's research, which once seemed so promising, aren't likely to produce The Cure

By DANIEL Q. HANEY Associated Press

Sunday, May 26, 2002

Boston -- Researcher Judah Folkman's mice are growing old and gray, famously cured of cancer. But people? Not yet and probably not real soon.

Developing new cancer treatments is a notoriously frustrating endeavor. Failure is the norm. Anything that stretches survival a few months is considered a victory.

But even by the inch-by-inch pace of this field, exploiting Folkman's invitingly simple idea for stopping cancer -- just shut off the blood supply -- has been slow going.

Six medicines based on his theory have finished human testing. Each was given to hundreds of end-of-the-line patients. Each failed to help in any meaningful way.

Eleven more are moving through large-scale studies. Although all seem promising enough to bring to this expensive stage of testing, no one knows how well any will work, if at all.

Even if one or more reaches the market -- which is possible in two to three years -- none is likely to be The Cure. That unlikely hope flourished four years ago but has largely faded.

This is, after all, cancer -- a disease that many doubt will ever be tamed by a single new medicine.

However, that was exactly the hope some had for Folkman's insight.

Medicines based on his research are designed to stop angiogenesis, the formation of new blood vessels that are necessary for tumors to grow larger than a pinhead.

Those who still believe he made a useful discovery say early disappointments are to be expected in a new field. But they wonder whether it will be written off because of unrealistic dreams of treatments dramatically better than the usual results of science's plodding progress, which is cancer medicines that sometimes work somewhat in some people.

"People have pretty much discounted the field," says Gwen Fyfe, Genentech's senior director of oncology. "There are waves of popularity and then disgust. We are in the wave of disgust for antiangiogenic drugs, and it's just as inappropriate as the wave of hysteria was."

The hysteria erupted in May 1998. Folkman had been working in obscurity for three decades at Boston's Children's Hospital, exploring tumor blood vessel growth in mice. Largely as the result of one astonishing quote, he became the most famous cancer scientist in the world.

It was in an optimistically worded front page article in the Sunday New York Times, and it was from James Watson, a Nobel laureate and co-discoverer of the shape of DNA: "Judah is going to cure cancer in two years."

Watson, for all his expertise, is not a cancer specialist, and many who are have ridiculed the thought that any single treatment would cure all kinds of cancer. Watson himself backed off. Still, the idea was planted.

Folkman's lab had discovered two natural compounds, endostatin and angiostatin, that appear to be powerful cancer fighters. When mice were given the drugs, their tumors shrank and disappeared.

High hopes dashed

These days, Folkman says, "We have dozens of mice downstairs that are getting old and gray because they had cancer, and we treated them. Some have been on endostatin their whole lives, and they're fine."

But these creatures' tumors are much easier to cure than humans'. Countless compounds over the years that looked fabulous in the lab have been ineffective in people.

Proving that a new medicine makes a difference against cancer can be difficult, but the challenge may be especially great for angiogenesis blockers. They weren't designed to kill cancer, so their benefits may be subtle and slow to emerge.

Because the drugs are being tested like regular chemotherapy, which involves looking for quickly shrinking tumors, many worry that some blood vessel blockers have been dismissed too soon. Instead of shrinking cancer, these drugs may stop it from growing, turning cancer into a stable, manageable disease, like diabetes. Appreciating this benefit could take studies that stretch on for years.

Furthermore, the first step in testing chemotherapy is to find the maximum tolerated dose -- the amount that stops just short of killing the patient. But many of the blood vessel blockers have no ill effects, so doctors are unsure what dose to take to the next stage of testing.

So far, no one has found a clear sign, such as a blood test, to tell whether the drugs are doing any good. Ideas such as sampling the number of tiny blood vessels growing in patients' tumors have led nowhere.

"The problem is, how do you develop a drug when you don't really know how it works, don't know how to administer it and are not sure how to measure it?" asks Adam Dicker, a radiation oncologist at Jefferson Medical College in Philadelphia.

Demand was massive

Without the attention four years ago, these drugs would probably succeed or fail out of public view, especially in early testing. But after Folkman's reluctant celebrity, demand for his drugs was overwhelming, especially for endostatin.

At the Dana-Farber Cancer Institute in Boston, one of four hospitals in the United States and Europe to do the first-stage safety testing, about 1,700 people begged for a chance at endostatin. Eventually, 25 were chosen.

"It was guaranteed to be disappointing," says Dana-Farber's J. Paul Eder. "The whole field has suffered in part by all of the very unreasonable expectations."

The study was never intended to answer whether endostatin works, although of course doctors looked for an effect. They saw only hints. Of 94 patients with 18 different kinds of cancer, five seemed to be helped, at least somewhat. Tumors shrank modestly in three, while in two others cancer receded in some places and advanced in others. Two who did best had rare pancreatic tumors.

Nevertheless, the results settled one issue. This was not The Cure.

In November, doctors began testing endostatin against insulin cell tumors. Eventually, 40 patients will get the drug at Dana-Farber and the University of California, San Francisco. A study of angiostatin against lung cancer is expected later this year.

Folkman believes that because these drugs work slowly, they will benefit patients with less advanced disease the most.

However, many doubt that blocking angiogenesis will be enough. Michael O'Reilly of M.D. Anderson Cancer Center in Houston, who discovered endostatin and angiostatin while in Folkman's lab, predicts they will have to be combined with other treatments.

"Angiogenesis inhibitors should never be considered a magic bullet, meaning you take a single pill and your cancer goes away forever," he says.

One reason: Cancers need growth proteins to sprout blood vessels, and these change over time. At first, one protein may do the job. But as cancers mature, they become sensitive to more and more growth proteins -- at least 15 are known -- and shutting off all of them is a challenge.

Many are trying to prove the basic concept of angiogenesis inhibition. William Li of the non-profit Angiogenesis Foundation says more than 200 companies are in the field, and more than 300 potential blood vessel blockers have been discovered. At least 40 are in human testing.

"The concept is great. The science is great," says Gerald Soff of Northwestern University. "Like everything in medicine, and cancer in particular, it takes time."

Copyright 2002 Journal Sentinel Inc. Note: This notice does not apply to those news items already copyrighted and received through wire services or other media
Provided by ProQuest Information and Learning Company. All rights Reserved.