good article on angiogenesis from Newsweek, 5/18/98. I'm reposting from Henry Niman's original post on the LGND thread. Note the good, non-technical explanation of the role of MMPs in angiogensis and cancer, and mentions of BBIOY, Ixsys, and AGPH's MMP products.
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Vessel inhibitors could open a new era in treatment.
By Geoffrey Cowley and Adam Rogers
Did last week's headlines give you a sense of deja vu? Endostatin and
angiostatin, the promising new cancer treatments that Dr. Judah Folkman
and
his colleagues have pioneered at Boston's Children's Hospital, aren't
the
first ones to spawn such an orgy of optimism. Interferon was the miracle
drug
of the 1960s. The 1970s brought us monoclonal antibodies. In the 1980s,
interleukin-2 was the craze. All of those agents have proved useful, but
none
has revolutionized cancer care. Most of the million and a half Americans
diagnosed with malignancies each year still suffer through some
combination
of surgery, radiation and chemotherapy. And though survival rates vary,
only
half of all cancer patients survive five years. Despite decades of
dazzlingly
sophisticated biomedical research, the knife remains our most potent
weapon
against cancer. According to oncologist George Canellos of Boston's Dana
Farber Cancer Institute, drug treatment still accounts for less than 10
percent of all recoveries.
Could these new treatments mark a turning point? Will drugs that keep
tumors from spawning blood vessels do to cancer what vaccines and
antibiotics
have done to many infectious diseases? Don't count on it. Most experts
view
the new "angiogenesis inhibitors" as possible complements to existing
therapies, not as complete alternatives. Yet Folkman's work has inspired
an
entire field of research, and the potential payoff is enormous.
The new approach is based on the simple yet critical observation that a
tumor needs a blood supply to grow. A genetic mutation may prompt a
normal
cell to divide uncontrollably, but unless the resulting mass can spawn a
network of vessels to deliver nutrients and oxygen, it will grow to the
size
of a pea and settle into a harmless, dormant state. Unfortunately, these
little sleepers can wake up. After sitting idle for months or even
years, a
pea-size mass may suddenly provoke nearby blood vessels to send out new
branches, or capillaries. That vascular flowering, known as
angiogenesis, is
supposed to occur only briefly during menstruation, pregnancy or wound
healing. But when tumors set the process in motion, it enables them to
grow
uncontrollably, invading healthy tissues and seeding the bloodstream
with
malignant cells.
No one knows why small tumors suddenly go angiogenic, but researchers
have
recently learned a lot about the process. As Northwestern University
cancer
researcher Noel Bouck has shown, healthy cells constantly regulate the
growth
of nearby blood vessels by generating chemical messengers known as
inducers
and inhibitors. The cells that line our vessels sport receptors for both
types of molecules. Normally the inhibitors predominate. But if a few
cancer
cells stop sending out their share of inhibitors, the cells in nearby
vessels
start proliferating wildly to form new capillaries. The new capillaries
aren't equipped to pierce the membranes that surround tumors, but they
have
receptors that enable them to glom on. And they bind readily with
enzymes
called MMPs, which serve roughly the function of drill bits. Armed with
MMPs,
the new vessels can bore into the tumor and set up a full-service link
to the
circulatory system.
As long as a tumor generates vessels, it can grow indefinitely--and the
bigger it gets, the more vessels it can generate. Fortunately, there are
many
ways to disrupt angiogenesis. Researchers have identified several dozen
agents that can thwart the process at one stage or another. At least 11
angiogenesis inhibitors are now being tested in humans. Many others are
at
earlier stages of development, and new ones are still being discovered.
Some of the candidate treatments are old drugs that happen to suppress
the
growth of new vessels. One example is Thalidomide, the morning-sickness
remedy that triggered a wave of birth defects back in the 1950s. In its
first
life, the drug kept some 10,000 babies from developing normal limbs.
Researchers are now hoping it will do something comparable to tumors.
Another
early entry is TNP-470, a synthetic analogue of the fungal antibiotic
fumagillin. Researchers have shown it can control both lung and skin
cancers
in mice. Unfortunately, many of these first-generation drugs have side
effects that could limit their use.
To get around that problem, some drugmakers are synthesizing more
narrowly
targeted compounds--molecules that disrupt angiogenesis by binding with
a
particular growth factor or jamming a certain receptor. Scientists at
Genentech are studying an engineered antibody that blocks VEGF, one of
the
signaling molecules that tumors use to make vascular endothelial cells
proliferate. And several companies are testing agents that could help
keep
nascent blood vessels from piercing the tumor membrane. Working with a
company called Ixsys, biologist David Cheresh of the Scripps Research
Institute has developed several molecules that keep new vessel cells
from
picking up MMPs (the drill-bit enzymes). His team is now preparing to
test
the drugs in people with inoperable tumors of the lung, colon, breast
and
prostate. Researchers at Bayer Corp., British Biotech of Annapolis, Md.,
and
San Diego-based Agouron Pharmaceuticals are already testing their own
MMP
inhibitors in people. The first ones could reach the market within five
years.
All of these agents do a reasonably good job of slowing blood-vessel
growth, but none of them performs like endostatin and angiostatin, the
molecules that Folkman's team is studying. Unlike most of the other
agents
now under investigation, the two statins are not test-tube inventions.
They're naturally occurring molecules that Folkman's colleague Dr.
Michael
O'Reilly found lurking in tumors.
It was a smart place to look. Surgeons have long known that removing a
patient's primary tumor can speed the growth of metastases. Large tumors
somehow keep small ones in check, and Folkman's group has long suspected
they
do it by suppressing angiogenesis. A large tumor may throw off more
inducers
than inhibitors, but the inducers disintegrate so quickly that their
effects
are felt only by nearby blood vessels. If the inhibitors lasted longer,
they
would stand a good chance of reaching, and suppressing, far-flung
metastases.
With that thought in mind, O'Reilly set about screening proteins from
cancer
cells in mice, and he found two that seemed to block angiogenesis. Last
year
he and his colleagues in Folkman's lab started testing them as cancer
treatments.
The results were dramatic. The researchers inoculated mice with one of
three cancers (melanoma, fibrosarcoma or Lewis lung carcinoma) and let
large
tumors develop. As expected, injections of endostatin quickly starved
the
tumors of blood, reducing them to tiny lumps. The tumors grew back
whenever
the mice went off the treatment. But unlike traditional chemotherapy,
the
endostatin worked just as well after repeated administration as it did
the
first time round--and to the scientists' surprise, it gradually beat the
tumors into submission. After a given number of treatment cycles (two
for
melanoma, four for fibrosarcoma, six for lung cancer), the tumors simply
stopped growing back. The researchers have since achieved similar
results, in
less time, by administering endostatin and angiostatin together.
No one knows just how these molecules block angiogenesis--let alone how
they permanently disabled the mouse tumors. And of course no one knows
whether either drug will have remotely comparable effects on people. "If
curing mice cancers were enough," says Dr. Donald Morton of the John
Wayne
Cancer Institute, "we would have cured cancer in the '60s." The
lab-grown
cancer cells used in mouse studies don't always behave like the "wild"
strains seen in the clinic. And tumors aside, mice and men have very
different vascular systems. A molecule that completely stalls
angiogenesis in
a mouse may slow the process only slightly in a person. When the person
gets
a large dose of endostatin or angiostatin--or any other inhibitor--his
body
may respond by churning out more inducers. And inhibitors that shrink
lung
tumors may prove worthless against breast tumors, or vice versa.
That's why most experts assume the new inhibitors will have to be
combined
with other forms of treatment. "Almost no cancer has been cured by a
single
agent," says Dr. Drew Pardoll of the Johns Hopkins University School of
Medicine. Fortunately, the arsenal is expanding all the time. Many
researchers are hopeful about turning patients' immune systems against
their
tumors. In preliminary studies, patients vaccinated against their own
advanced melanomas have raised their chances of surviving five years
from 5
percent to 40 percent. Gene therapy may soon offer other weapons. This
week,
researchers at the M.D. Anderson Cancer Clinic in Houston will report
early
success at treating advanced lung, head and neck tumors by infecting
them
with genetically altered cold viruses.
Yet the angiogenesis inhibitors have one advantage that the other new
therapies lack: they don't have to eradicate every tumor cell in the
body to
succeed. If some combination of the new agents could successfully police
the
blood vessels, a few stowaway cancer cells would pose no real threat.
Policing the blood vessels is bound to be complicated, but it may prove
easier than trying to eradicate tumor cells. As the endostatin mouse
study
makes clear, healthy endothelial cells make excellent targets for
treatment
because they don't constantly change the way cancer cells do. A drug
that
checks their growth once should keep working indefinitely.
And it should work without poisoning the patient. Though traditional
chemotherapy quickly loses its effect on cancer cells, it continues to
kill
healthy ones. People relying on angiogenesis inhibitors could face
serious
side effects--including Thalidomide-style birth defects and an inability
to
heal common wounds. But as University of Toronto cancer-biologist Robert
Kerbel observes, disrupting angiogenesis is rarely dangerous--for blood
vessels rarely have a good excuse to proliferate. "We used to hope that
the
drugs we developed would kill more tumor cells than normal cells," he
says.
"Now we can hope for something better." Unfortunately, it's still too
soon to
bank on it.
With Andrew Murr and Claudia Kalb
Newsweek 5/18/98 Lifestyle/Of Mice and Men |
