A headline in the
New York Times unexpectedly pushed the work of Judah
Folkman, MD, into the limelight recently, making his >30 years of
research into angiogenesis seem like an overnight success. It is a
position that puts Folkman ill at ease. He is not comfortable with
hyperbole about the research he has conducted at Boston's Children's
Hospital and Harvard University Medical Center.
The New York Times front-page story drew a storm of
enthusiasm and then skepticism. Folkman appeared bemused by the flurry
of interest. He has been working quietly in the field of angiogenesis
for so long that he had not anticipated the hubbub that the story
caused. And he was not ready to have much known about his study until
it had been proven in thousands of patients. Judah Folkman is the first
to say that he can cure cancer—in mice.
Others are more generous in their praise. James Willerson, MD, editor
of Circulation, medical director at the Texas Heart
Institute, and chairman of the department of medicine at the University
of Texas Medical School at Houston, called him "the father of
angiogenesis." Folkman gave the annual Willerson Lecture at the
University of Texas Health Science Center at Houston. Dr Isaiah Fidler,
chairman of the department of cell biology at the University of Texas
M.D. Anderson Cancer Center, is an admiring collaborator of Folkman's.
"He is a beacon of hope. He is a national treasure. He is intuitive,
brilliant, and unafraid of the unknown. He persisted, and he got
there," Fidler said.
Although his work in the field of cancer has garnered the most
attention, Folkman, in an interview with Circulation, said
he began by trying to unravel the puzzle of angiogenesis. He and Fred
Becker, MD, were trying to grow thyroid tumors in rat tissue while they
were conducting research while in the US Navy. The implanted cancer
cells grew to a minuscule size and then stopped growing. From that,
Folkman and Becker theorized that tumors could not grow without a blood
supply. And from that theory grew an entire field of angiogenesis.
"There was the conventional wisdom that tumors don't need new blood
vessels, that they could grow on the old ones," Folkman said. "So
basically, we were trying to work out all the methods of how you get
angiogenesis."
That meant identifying the proteins that promote the growth of new
blood vessels. "The first angiogenic protein took us about 6 years to
purify," said Folkman. The first publication about that protein
(basic fibroblast growth factor) was in 1984. "There are now at least
14 others," he said. "Those were the things that turned it
[angiogenesis] on," he said. "Those we had in the 1980s, but no
one could turn angiogenesis off."
In animal studies, researchers produced the growth factors that turn on
angiogenesis, and the animals' cancers got worse—an action mirrored
in people, Folkman explained. "If you look at breast cancer patients
when they are first diagnosed, the only angiogenic factors the tumors
make are VEGF [vascular endothelial growth factor] or
FGF [fibroblast growth factor]." But he found that when such women
developed metastases, the tumors were making 4, 5, or 6 angiogenic
factors.
In heart disease, researchers are studying ways to encourage
angiogenesis, but cancer researchers want to starve tumors by stopping
the generation of new blood vessels. "Angiogenesis is really hard to
turn off," Folkman said. Until the mid-1980s, he said, researchers
knew only how to turn angiogenesis on. "That was the status of the
field," said Folkman. "And then began the discovery of the first
molecules that could turn off angiogenesis, but they weren't that
powerful.
Newer antiangiogenesis agents are powerful enough to regress tumors.
Those closest to being used clinically can slow the growth of tumors
but cannot eradicate them, Folkman said. "In the 1980s, we
basically thought the angiogenesis inhibitors would never
kill a tumor. They would be adjuncts. That's where we thought the
field would settle out—as an adjunct to chemotherapy."
And then in the early 1990s came the discovery of a set of proteins so
effective that they eradicated tumors in mice. "One is angiostatin,
and one is endostatin," said Folkman. Research on other such proteins
has not yet been published.
The discovery of angiostatin arose from a puzzling mystery that was
well known in the cancer field. In some cancers, the disease expressed
itself as a strong, primary tumor. But when that primary tumor was
removed, the body quickly became dotted with metastatic tumors.
Folkman, like others, thought that perhaps the primary tumor itself
secretes a factor that inhibits the growth of new tumors.
Michael O'Reilly, MD, a young physician in Folkman's laboratory,
discovered angiostatin, a fragment of the protein
plasminogen. Angiostatin is a naturally occurring protein.
The first article on angiostatin was published in the journal
Cell in 1994. Endostatin was discovered in 1997, Folkman
said. "The protein could regress tumors in mice with no escape. We
have been trying to find a tumor we could not regress."
The kind of tumor does not matter because the drugs do not work on the
tumor cells, said Folkman. "They work on the
endothelium that the tumor recruits. All you do is
raise the dose of the drug to match the angiogenic
production by the tumor. There is no top dose to these drugs.
When the tumor regresses, that's what you use.
"And there's no toxicity. No one believes it because we haven't
been in a place before where that is possible. It is a different way to
treat tumors.
"In medical practice, there is sometimes a disconnection between
knowledge of disease and the best treatment," Folkman said. "Who
would have thought that microscopic endothelial cells
would have had such tight control over tumor mass?"
But Folkman is the first to point out that his treatment, while
promising, is far from proven. "We can treat mice," he said. "The
problem is that translating from mice to people is full of failure and
full of pitfalls."
In mice, he said, tumor burden is not a problem. "You can cure mice
with bad tumors, like Lewis lung carcinoma." This particular cell
line kills mice with metastases, he said. But a tumor that would
translate to 1.5 pounds in a human shrinks to nothing in a mouse when
it receives endostatin.
If you stop the treatment, the tumor comes back. But after a few
cycles, the tumors no longer recur, said Folkman. "They are
dormant," he said. The combination of endostatin and angiostatin can
eradicate the tumors entirely.
Folkman anticipates a publication detailing the outcome of those
combination studies when the last of the mice die of old age. "There
will be no criticism. Anytime you sacrifice them [the mice] before
that, [the critics] said, `Oh, they would have died. ... You did
it prematurely.' That's why we put a promissory note in our
Nature paper."
But it is only a promise, said Folkman. "When the new, powerful
[antiangiogenesis factors] get in the clinic ... if they do ...
they will probably be used most immediately to add to chemotherapy."
They would also be used as an adjunct to radiotherapy, vaccine therapy,
and immunotherapy. "We can keep them [tumors] dormant, and they
[antiangiogenesis factors] can wipe them out." Angiogenesis is not
going to displace anything in the near future, Folkman said.
"How unpredictable science is!" Folkman said. "One day the
[National] Heart [Lung and Blood] Institute looked up to find that
big studies [in that field] were going on all over the place with a
molecule that was found in a study funded by a grant for cancer
[research]."
He said, "I'm not a cardiologist. But I'm working in a field
important in cardiology." That was proven, he said,
by a February 24, 1998, publication in
Circulation1 that outlined "an
important advance." The study showed that injections of fibroblast
growth factor increased the growth of blood vessels after patients had
undergone heart bypass surgery.
Jeffrey Isner, MD, at Harvard University Medical School has been using
VEGF to treat coronary artery disease, as has Todd Rosengard at
Cornell University Medical Center in New York. "It is too early to
say if this will ever be used as first-line therapy," Folkman said,
but the findings are important because they represent a new way
of looking at heart disease.
Many questions remain: Is it better to inject the protein plasmid with
naked DNA or viruses that carry the genes into cells? Should it be done
after coronary artery bypass grafts,
percutaneous transluminal angioplasty, or
percutaneous transmyocardial reperfusion? With many new
groups working on the problem, such questions should be answered in the
near future, said Folkman.
And then there is the question of whether plaque formation is
angiogenesis dependent, he said. At the behest of the US Food and Drug
Administration, Folkman began a small project to study the
mechanism of plaque angiogenesis. In that program, one of his
postdoctoral associates, Robert J. D'Amato, MD, found evidence that
thalidomide is an angiogenesis inhibitor. Years of using
thalidomide to treat Hansen's disease had convinced doctors
at the Carville colony in Louisiana that it protects against myocardial
ischemia, according to Folkman. "The alternative explanation
is that leprosy protects against cardiovascular
disease," he said. But if angiogenesis is crucial to plaque
formation, the identification of antiangiogenesis factors might help
eliminate the stenosis that is at the heart of coronary
artery disease, said Folkman.
If drugs can be found to block neovascularization in plaque, then there
may not be a need for coronary collaterals, he said. But that
is only if plaque growth can be shown to be dependent on angiogenesis.
Studies are now under way to determine how important angiogenesis is in
such growth.
Before the Schumacher report in
Circulation,1 a few laboratories were
working in the field of angiogenesis induction as a method of dealing
with vascular problems. Since that report, which Folkman calls
"landmark," the number of laboratories doing such work has
skyrocketed.
It all demonstrates the sheer unpredictability of science, said
Folkman. He waits for the next step with anticipation and excitement.
Yet, he knows the difficulty involved in that next step of taking a
treatment from animals to human patients. "Anyone knows how hard it
is to translate from the lab to the clinic," he said.
References
1.
Schumacher B, Pecher P, von Specht BU, Stegmann T.
Induction of neoangiogenesis in ischemic myocardium
by human growth factors: first clinical results of a new treatment of
coronary heart disease. Circulation. 1998;97:645–650.
© 1998 American Heart Association, Inc.
Cardiovascular News
Two Sides of the Same Coin
Stop Angiogenesis for Cancer and Encourage It for Coronary Artery Disease
-Interferon was the first." It turns out that interferon
is useful for treating life-threatening hemangiomas in
newborns—hemangiomas that occur in the brain, liver, or the
area surrounding the heart.
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