This is a very good article on Judas Folkman and how his drugs endostatin
and angiostatin were discovered.
Within a year, if all goes well, the first cancer patient will be injected
with two new drugs that can eradicate any type of cancer, with no obvious
side effects and no drug resistance -- in mice.
Some cancer researchers say the drugs are the most exciting treatment that
they have ever seen. But then they temper their enthusiasm with caution,
noting that the history of cancer treatments is full of high expectations
followed by dashed hopes when drugs with remarkable effects in animals are
tested in people.
Still, the National Cancer Institute has made the drugs their top priority,
said Dr. Richard Klausner, the director. Klausner called them "the single
most exciting thing on the horizon" for the treatment of cancer.
"I am putting nothing on higher priority than getting this into clinical
trials," Klausner said. The mouse studies are "remarkable and wonderful," he
said, and "very compelling." But he pointed out that the studies were in
mice and so, in humans, he said he wanted to emphasize "the if's."
The new drugs, angiostatin and endostatin, work by interfering with the
blood supply tumors need. Given together, they make tumors disappear and not
return.
Dr. James Pluda, who is directing the cancer institute's planned tests of
the drugs in patients, said he and others at the institute were
"electrified" when they heard the drug's discoverer deliver a lecture about
the newest results. "People were almost overwhelmed," Pluda said. "The data
were remarkable."
Although the discovery of the drugs, and some of their effects, have been
reported over the past few years, Pluda said that "if people understood how
many steps ahead" the research was compared to what had been published,
"they'd be even more in awe."
But Dr. Jerome Groopman, a cancer researcher at the Harvard Medical School,
was wary. "We are all driven by hope," Groopman said. "But a sober scientist
waits for the data." And until the drugs are given to humans, he said, the
crucial data simply do not exist.
So far, the drugs are the only ones ever tested that can seemingly eradicate
all tumors in mice, even gigantic ones, equivalent to a two-pound growth in
a person. The best that other cancer drugs have done is slow the growth of
these large tumors. Mice are the traditional test animals in cancer
research.
But even the drugs' discoverer, Dr. Judah Folkman, a cancer researcher at
Children's Hospital in Boston, is cautious about the drugs' promise. Until
patients take them, he said, it is dangerous to make predictions. All he
knows for sure, Folkman said, is that "if you have cancer and you are a
mouse, we can take good care of you."
Other scientists are not so restrained. "Judah is going to cure cancer in
two years," said Dr. James Watson, a Nobel laureate who directs the Cold
Spring Harbor Laboratory, a cancer research center on Long Island. Watson
said Folkman would be remembered along with scientists like Darwin as
someone who permanently altered civilization.
The long trail to the discovery of the new drugs began more than 30 years
ago when Folkman became obsessed by what many saw as a quixotic notion: that
cancers cannot grow beyond the size of a pinhead unless they have their own
blood supply. If he could block a tumor's blood supply, he reasoned, the
tumor should shrink to a minuscule size.
The first major break in the efforts came a decade ago when Folkman and his
collaborators found drugs that did what he envisioned. He called them
anti-angiogenesis drugs because they stopped the process of developing new
blood vessels, or angiogenesis. They slow tumor growth in animals but do not
eradicate the tumors. Early results in patients indicate that the drugs may
slow human cancers, too. Dozens of companies are now developing such drugs.
The results with these weaker drugs were "a proof of principle," said Dr.
Bart Chernow, a professor of medicine and dean for research and technology
at the Johns Hopkins University School of Medicine. Chernow is a founder of
Entremed, a company in Rockville, Md., that was formed to make and market
angiostatin and endostatin as well as some of the weaker drugs that can slow
cancer growth.
But the real breakthrough -- and the two new drugs -- came from Folkman's
efforts to understand a peculiar phenomenon that has been known to cancer
surgeons for 100 years: sometimes a patient will have a single tumor, with
no evidence whatsoever of metastases, the satellite cancers that can pepper
a patient's body. A doctor will remove the tumor and all will seem fine. But
then, a few months later, a whole series of metastases will appear, grow,
and kill the patient.
In 1989, Folkman proposed a reason for the effect, which he wrote on a large
white board in a room where his laboratory group had its weekly seminars. Is
it possible, he asked, that a tumor could be making both stimulators and
inhibitors of blood vessel growth? If so, the inhibitors might travel
through the bloodstream, squelching metastases. When the large tumor was
removed, it would no longer be a source of inhibitors, allowing the tiny
metastases to proliferate.
Folkman tried to get one of his doctoral or post-doctoral students to work
on that idea. "Each Friday, at our meeting," he said "I would say, 'Here's a
great experiment.' But no one wanted to work on it." It seemed too wild,
Folkman said, too unlikely to result in findings that would end up in a
scientific journal, a major goal of young scientists.
Then, in 1991, a post-doctoral student, Michael O'Reilly, decided to take on
the challenge. O'Reilly focused on a particularly deadly mouse cancer that
grows to the equivalent of a two-pound tumor in a person.
As long as mice had the large tumor, they had no signs of metastases. But
five days after the tumors were surgically removed, metastases invariably
sprang up in the animals' lungs. Within 15 days, the animals would be dead,
their lungs packed with large red tumors, like grapes.
Eventually, after arduous work in collaboration with chemists, O'Reilly
discovered that the large tumors made a substance that stymied the growth of
other tumors. This substance showed up in the animals' urine, but was
present in such minute quantities that O'Reilly had to collect 10 quarts of
mouse urine to obtain 30-thousandth of an ounce of the mysterious substance.
It turned out to be a piece of a larger and very common protein,
plasminogen, that the body uses in blood clotting. Folkman named it
angiostatin.
Apparently, cells can use the plasminogen gene for two purposes: they can
use it at its full length to make plasminogen, or they can use just a piece
of it and make angiostatin. Plasminogen does nothing to stop tumor growth.
The question was, would angiostatin?
Folkman and O'Reilly discovered that angiostatin also appears, in minute
quantities, in human blood. Using outdated human blood discarded by the Red
Cross, they extracted enough angiostatin to treat mice. Then they began
their experiment.
They had 20 mice with large tumors on their backs. The investigators removed
the tumors and then injected half of the mice with angiostatin each day and
the others with salt water, as a comparison.
After 15 days, the researchers killed the mice and cut them open. As more
than a dozen scientists gathered around a table in the laboratory, O'Reilly
opened the first mouse. It had huge tumors filling its lungs. Then Folkman
checked a notebook to see what the animal had received: salt water. They
looked at the next mouse. No tumors. Folkman checked to see the treatment:
angiostatin. And so it went. All 10 of the mice that had been injected with
angiostatin were free of cancer. All 10 of those that had been received salt
water had huge new tumors.
The room was buzzing, the scientists were grinning. Folkman said. Everyone
in the room knew what the results meant, and they were elated. They
responded, he said, like men at a football game. "Everyone clapped O'Reilly
on the back," Folkman said.
Then the researchers found a second protein fragment, secreted by tumors,
that also squelches metastases, Folkman said. It was a piece of a different
protein, collagen 18, that is in all blood vessels but by itself has no
effect on cancer. They named the collagen fragment endostatin.
"It was even more potent than angiostatin," Folkman said. If he gave it to a
mouse with a huge tumor, he said, the equivalent of one weighing a pound and
a half in a human, endostatin would shrink the cancer down to a microscopic
size.
Moreover, tumors never became resistant to endostatin, said Folkman, who
added that he had given the drug to mice with large tumors and they had
shrunk to almost nothing. He stopped the drug, he said, and the tumors grew
back. Then he gave the drug continuously for the rest of the animals' lives.
The tumors remained small and harmless and the animals remained healthy.
Dr. Robert Kerbel, a cancer researcher at Sunnybrook Health Science Center
in Toronto, said he was not surprised that the cancers never became
resistant to endostatin. Tumors become resistant to chemotherapy drugs,
Kerbel said, because cancer cells constantly reshuffle their genetic
information. The result, he said, is that the tumors spin off mutant cells
that resist the drugs and, ultimately, the tumors grow back, invulnerable.
But, Kerbel said, angiostatin and endostatin do not act on tumors. Instead,
they act on normal blood vessels that feed tumors. And normal cells, he
said, do not reshuffle their genes and so do not develop drug resistance.
That is why chemotherapy drugs continue to devastate normal cells -- causing
bone marrow suppression, loss of hair, nausea and vomiting -- even when the
cancer cells have grown impervious to their effects, Kerbel said.
Then Folkman discovered that he could actually obliterate tumors in mice
with his new drugs. He gave endostatin and angiostatin together, treating
mice for 25 days. To his surprise, Folkman said, "there was no tumor left --
we couldn't even find it with a microscope." The tumors, he said, "were
eradicated."
And the drugs seem to have no side effects, at least in mice, something that
Folkman acknowledges is hard for researchers to believe. But, he said, he
had given mice up to four times the doses needed to eliminate cancer and
could not find any adverse effects. These two human proteins may be, he
said, "exquisitely aimed -- we do not know why -- at cancer."
In contrast, Folkman said, mice become very ill when they receive commonly
used chemotherapy -- their hair falls out, they bleed, they refuse to eat.
For the past four years, Folkman said, he and his colleagues have found that
all tumors responded to the drugs in the same way. Even leukemia, a blood
tumor, responds, he said, because it turns out that leukemia needs to form
new blood vessels in the bone marrow to grow. Leukemia tumors grow on these
blood vessels, "like berries on a bush," Folkman said, shedding cancer cells
into the blood.
But Folkman is the first to urge caution in leaping to conclusions about
what might happen when patients try the drugs. "Going from mice to people is
a big jump, with lots of failures," he said.
Hopes were high for chemotherapy drugs that worked well in mice but turned
out to be less successful in people. Therapies that used the immune system
to rid the body of cancer also worked in mice but were disappointing when
they were tried in people. Gene therapy treats mouse cancer, but has had
limited success in people. From bitter experience, most cancer researchers
have learned to be leery of what one called "that four letter word" -- cure. |
