Folkman Battles Cancer, Spotlight

The cure for cancer might be modern medicine's holy grail, the greatest medical discovery since the polio vaccine.

Andrus Professor of Pediatric Surgery at Harvard Medical School (HMS) M. Judah Folkman was prepared to try and fight cancer. He was not prepared to be touted as the next Jonas Salk.

Folkman, who has spent his professional career researching the growth of blood vessels, announced in the November 1997 issue of Nature that drugs tested in his lab had caused tumors in mice to regress to microscopic size.

About one year later, a front-page article in the New York Times led a media blitz that managed to blow even this important discovery out of proportion, making Folkman sound steps away from a cure for cancer in humans.

In the year since that article was published, Folkman has had a rocky time as a medical celebrity.

Other labs had trouble duplicating his results. And he must continually but cautiously explain his work to the press and the public, making it clear that there are no miracles up his sleeve.

Scientific Successes

Since the late 1960s, Folkman's research has focused on the process of angiogenesis, whereby the body constructs new blood vessels.

Though his work did not originally have to do with cancer, Folkman soon realized that the formation of new blood vessels was crucial to tumor growth.

"For a tumor to grow beyond the size of a pencil eraser, it recruits its own blood supply, and it does that day after day," Folkman says.

Because the formation of new blood vessels in normal adults only occurs in special situations--wound healing, after a heart attack, and during menstruation--a process to suppress the development of these vessels logically prevents the formation of cancerous tumors.

Angiogenesis not only allows tumors to grow but also makes it more likely that they will metastasize, or spread through the vessels into the bloodstream and other parts of the body.

But even after a small tumor forms, cutting off its blood supply could render it harmless by preventing it from growing or spreading.

"You can have an in situtumor all your life and never know about it. In situcancer is not usually harmful because it does not metastasize," Folkman says.

It was Folkman--also director of the surgical research laboratory at the Children's Hospital Medical Research Center of HMS--who first hypothesized in the 1970s that cutting off a tumor's blood supply would essentially starve a tumor, potentially saving the lives of cancer patients.

But at first, scientists could not develop angiogenesis inhibitor drugs because there was no established test for the drugs' effects on the growth of blood vessels.

Three years after his initial discovery, in 1975, Folkman and colleague Henry Brem discovered the first angiogenesis inhibitor molecule in cartilage. Researchers, including Folkman, had to learn to culture blood vessels and try to test angiogenesis inhibiting compounds.

From Folkman's original work, study of angiogenesis and its medical uses has spread to labs across the globe.

Folkman says that of the 20 angiogenesis inhibitors now being administered to patients in clinical trials, seven have reached Phase III, the stage that comes immediately prior to obtaining approval from the Food and Drug Administration (FDA).

But endostatin, a compound discovered in Folkman's lab in 1997 by Michael O'Reilly, a researcher at the Dana-Farber Cancer Institute, has led the pack.

It has raced through tests on mice to the beginnings of human clinical trials so quickly that Folkman says "It must be a record."

After a report on endostatin was published in the science journal Cell in January 1997, the protein's crystal structure was described in the fall of 1998 by Loeb Professor of Biochemistry and Biophysics Donald C. Wiley and associate Wuan-Hua Ding in the Department of Molecular and Cellular Biology. Clinical trials with human patients are slated to begin at Dana-Farber, Brigham and Women's Hospital, and Massachusetts General Hospital in just a few months.

It was endostatin which brought Folkman to the front page of the New York Times.

Under the Microscope

Six months after the Nature report was published, the New York Times picked up the story and ran it--not in the Science section, where Folkman thought it would appear, but plastered above the fold on the front page.

Folkman and his colleagues were guardedly optimistic about transferring the positive results of treatments of mouse tumors--the experiment on which the Times had seized--to human cancer patients and were leery of the raised expectations such press coverage could bring.

The media's response to his work has been puzzling to Folkman, who stresses he never used the word "cure"--"only the New York Times did." He also says his positive results in trials with mice did not seem to warrant the front page of the Times, since the so-called "third generation" drugs used in his research--angiostatin and endostatin--have yet to be tested in humans.

To jump to conclusions about the drug's potential success in humans based on their observed effects on mice, says Folkman, is not right.

Folkman says he told the New York Times reporter who wrote the article that it was imperative to use the word "mice" in the headline and to make clear that cancer remission had only been documented in rodents, which the writer did.

"I asked them to print, up front, `If you are a mouse and you have cancer, we can take good care of you,'" he says, "but when it went out the next day [on television and in other newspapers] it was overlooked."

Roller Coaster Ride

After the Times article ran, researchers at the National Cancer Institute tried in vain to duplicate the results obtained in Folkman's lab.

Negative press coverage of this failure was then turned upside-down by the revelation that some researchers finally had gotten similar results. The press was Folkman's friend again, though he says very little had actually changed.

On Feb. 12, 1999 the Times published an article describing the new success, and Folkman's cause received renewed attention from biopharmaceutical companies, universities and other research institutions worldwide.

Folkman says he believes part of the problem in responsibly reporting the results of scientific research is the intrinsic challenge facing journalists who specialize in science when they deal with medical issues.

"Science writers serve a very important function, which is to translate advances in science for the public, which is paying for that in grants," he says. "The only difficulty is that when research comes close to moving from the laboratory to patients, it can create raised expectations and let people down."

Folkman explains that although lab research with angiogenesis drugs has already obtained favorable results, it will most likely take several years to receive FDA approval, with additional time for manufacturing and distribution.

Still, since it takes an average of 15 years for experimental drugs to make it out of the lab and to patients, Folkman's endostatin is tantalizingly close to distribution.

In fact, according to the Pharmaceuticals Researchers Manufacturers of America, only one out of 1,000 compounds tested make it to clinical safety trials in human subjects. Of those, approximately one out of 20 become FDA approved.

"A cancer patient whose tumor is not responding to conventional therapy can go into clinical trials of new drugs, but there are sometimes waiting lists and shortages," Folkman says. "Whenever lab discoveries come close to application, you have to be super-extra careful...because media coverage can increase expectations."

Dealing with the Media Blitz

Donald E. Ingber, an associate professor of pathology at HMS and a research associate in pathology and surgery at Children's Hospital, has worked with Folkman for 15 years and has had a front-row seat during the recent media events.

"The media may be trivializing [Folkman's] contributions by putting all the pressure on one compound, endostatin, to be a silver bullet in the clinic. This is unfair," he says. "[Folkman's] contributions to both angiogenesis inhibitors and stimulators in clinical trials cannot be underestimated."

Ingber adds that to him it seems the media flurry surrounding endostatin trials and Folkman's recent work is attributable at least in part to the perceived novelty of the results.

"The media all report news in relation to these new drugs as if they are hearing it for the first time, which they of course are," he says.

"The reality is that almost all of the angiogenesis inhibitors have been found to be generic, not to induce drug resistance, to have low toxicity, et cetera, in animals," he adds. "This was first shown with TNP-470 many years ago."

It was Ingber himself who, as a post-doctoral fellow, discovered the drug TNP-470, the first angiogenesis inhibitor from Folkman's lab to enter human clinical trials.

In contrast to newly discovered, highly publicized proteins like endostatin, Ingber says, TNP-470 has actually already been tested in humans in clinical trials conducted since 1992. In April 1998, the first complete tumor remission in a human using this drug was published as a case report in New England Journal of Medicine, and the drug will likely be entering Phase III trials very soon.

Still, Ingber says, "I think Folkman is truly the pioneer in this field and I guess the media feels that if he believes this [endostatin research] is the most exciting thing around, then they should give it their greatest attention. From this perspective, it is a reasonable response."

Long-Term Possibilities

Despite the confused coverage of Folkman's work in the media, Ingber says endostatin has the potential to one day be a very important weapon in the fight against cancer and other diseases.

Endostatin has been shown to induce the complete regression of tumors whereas other drugs may only prevent metastasis or halt growth when used alone.

And theoretically, endostatin patients should be able to undergo long-term treatment with little to no side effects, since the protein occurs naturally in the human body and will therefore not be rejected by the host.

In addition, "many of the drugs which are in clinical trials and which the media has not focused on, also were a direct product of Folkman's work," Ingber says, citing TNP-470 and thalidomide as examples.

But while Ingber gives Folkman due credit, he questions the media's choice of how it focuses its coverage of anti-angiogenesis research.

"The media wants a silver bullet, but it is virtually impossible to obtain one, especially given how cancer trials are designed...using end-stage patients who have failed all other therapies with large tumor mass, et cetera," he says.

Ingber also points out that "sometimes it is a lot easier for the media to sell a simple dream than the complexity of reality."

He explains that the results of Folkman's work so far are based entirely on animal studies, and that most reported human results so far have come from Phase I trials, where the researchers mainly attempt to identify a drug's toxicity while the patients receive escalating doses.

"Since the drug must be given alone in Phase I so that the results are interpretable...no one has seen one hundred percent of tumors regress and disappear when these drugs are given alone," he says. "These are often end-stage cancer patients with tumors that have become modified by many past chemical and radiation therapies."

"This type of result is of no value to the mainstream media because it is not a simple story to sell," he adds.

However, from his own work and observation of Folkman's work, Ingber says he believes in the end angiogenesis inhibitors will help in the management of cancer and other disorders.

"I am a firm believer that cancer will not be cured per se,"he says. "Rather it will be managed much like we now manage tuberculosis or diabetes. In sum, if [anti-angiogenesis therapy] is not a cure it will break the back of the disease."

Folkman also says that angiogenesis research may offer a broad range of potential benefits, pointing out that cancer patients are not the only people who stand to gain from anti-angiogenesis work.

"A lot of diseases turn on angiogenesis and don't turn it off," he says. "Arthritis, where vessels grow on the joints; blindness in diabetics; endometriosis, where there's bleeding in the abdomen from the lining of the uterus gone up the tube."

Drugs like endostatin could make very useful and effective treatments for these diseases since, as Folkman says, they are "very safe, like insulin, but also potent."

The lightning speed at which work on angiogenesis has progressed, as well as the immense promise his and his colleagues' research holds for the future of medicine, prompted Folkman to make an analogy to another technological feat no one had thought possible.

"It's sort of like the Wright Brothers," he says. "When they took off on their first flight, it only took 12 seconds."

But what followed proves beyond a doubt that the seemingly impossible--be it human flight or the management of incurable diseases--may sometimes be achieved through passion and dedication, two attributes Folkman has in spades.