When Cancer Escapes the Prostate: New Strategies for
Drugs to cut off spreading cancer's blood supply, a molecular grenade
that detonates PSA-making cells, and new tests to predict aggressive cancer
-- they're all part of an impressive, multi-pronged plan of attack.
Some prostate cancer cells are practically homebodies; their growth
is creeping, their advance local. But other cells can't wait to leave
the nest -- to hitch a ride on the bloodstream headed for points
north. This restlessness has a name -- micrometastasis -- and it
can be lethal.
Micrometastatic cells specialize in the quiet exit; these tiny flecks
of cancer slip out of the prostate in such small numbers that they're
invisible -- and impossible for doctors to detect, even during
surgery for what appears to be localized disease.
These cells are the scourge of prostate cancer treatment: Once they've
managed this breakout, escaping via the bloodstream to the lymph nodes
or spine, prostate cancer can no longer be cured.
But scientist John Isaacs, Ph.D., professor of urology and oncology --
every bit as persistent and determined as the enemy, metastatic cancer --
is undaunted. He's spent his career stalking these cells, working to master
their habits and properties, and developing an impressive, multi-pronged
plan of attack.
Which Cancers are Likely to Roam?
Pity the meteorologists trying to forecast the weather during tornado
season in Kansas: Despite all the technological advances that allow them
to track storm patterns, in the end, all they have is probability --
the odds that a tornado will develop, and an informed guess about
when and where it might hit.
Scientists studying prostate cancer face a similar predicament.
Although landmark tables developed at Hopkins using PSA level,
Gleason grade and clinical stage (see story on page 14) have given
men and their doctors an unprecedented ability to predict the extent
of cancer, these markers are most helpful "when the cancer looks
either terribly aggressive or extremely aggressive," says Isaacs.
"The difficulty is, many men fall between those two extremes."
Unfortunately, some of these men -- and there's no way to know
for certain which ones -- diagnosed with curable disease have cancer
that has already left the prostate. "There aren't any techniques
now to detect that level of cancer, because it's just so small,"
says Isaacs. "But it means that local surgery alone isn't going
to be curative. What we're trying to do is come up with a
molecular mechanism for predicting cancer's aggressiveness."
Over the last decade, Isaacs has cultivated what probably is the
world's richest nursery of prostate cancer cell lines -- nearly
30 distinct varieties -- which he uses in layers of experiments
ranging from tissue cultures to a spectrum of animal models
(including mice with no immune systems, in which human tumors
can grow). "We've got the full range," he says, human
and animal tumors that are "highly metastatic, not metastatic,
hormone-independent, hormone-dependent, well-differentiated and
poorly differentiated," and everything in between. (In fact, one
rat model of prostate cancer, which Isaacs developed when he
was a postdoctoral fellow in the lab of Donald S. Coffey, Ph.D.,
has become the most widely used system for prostate cancer in the
world; Hopkins has supplied it to more than 200 research
John Isaacs, Ph.D.
Isaacs is using the most aggressive cells in his encyclopedia
collection for a sophisticated series of experiments in tissue
culture and animals, designed to find genetic restraints for
cancer -- molecular fences to keep these cells from roaming.
Through painstaking lab work, he and colleagues are adding
human chromosomes from normal cells to these nasty, metastatic
cancer cells. It's a form of "roll call," in which they're testing,
one by one, all 23 pairs of chromosomes in the human body. They're
looking for signs of inhibitory effect -- any clue that something
(a gene or genes) on one of these chromosomes can either
suppress the cancer's growth or its ability to metastasize. So far,
they've earmarked for further study a handful that look promising,
including chromosomes 5, 8, 10, 11, and 17. "We've been able
to map areas of chromosomes with genes that actually suppress
metastatic ability," Isaacs says. Among the most exciting is
on chromosome 11, where "we've not only identified the region"
(the cancer-suppressing "neighborhood" is on the chromosome's
short, or petite arm, called the "P" arm) "but we've cloned
and tested the genes. The first gene we identified is called
Like a sandbag that helps keep a hot air balloon on the ground, KAI
(pronounced like the Greek "chi")-1 suppresses metastasis. It's
product is found in normal cells. But at some point, on a cell's
journey from normal to metastatic, it disappears; the cell stops
making it. Isaacs and colleagues have developed special antibody
stains that recognize KAI-1's distinctive handiwork (telltale
proteins that it makes), to search for the gene in prostate cancer
biopsy specimens. The idea is that if a cancer is not making
enough of it, it may be well on its way to metastasis -- and this
stain could help predict aggressive cancer.
Chromosome 11 has proved a fertile field; it's yielded another
promising gene, called CD44. Here, too, is a gene, found in the
prostate epithelial cells, that makes a metastatic-blocking
substance. "When these cells become cancerous, and when they
become highly metastatic, they turn off the production of this
protein," says Isaacs. "The gene is still there. With both
KAI-1 and CD44, the genes are physically still present -- they're
just not expressed." Isaacs hopes to find a few more of these
genetic markers. Then perhaps one day, if tests (such as the reagent
stains his lab has developed) show that a cancer has systematically
inactivated several of the genes that could keep it in check, this may
be a strong indication for aggressive treatment (However, before this
becomes a widely used form of testing, much more study is needed,
One Way to Stop Cancer: Cut Off the Supply Line
So: After a radical prostatectomy, a man turns out to have
micrometastases, invisible offshoots of tumor taking root at satellite
locations in the body. His cancer lives; chances are, it will
continue to grow. "What are you going to give him? Hormone therapy
is very helpful, and in fact, it gives great palliation," says Isaacs.
"But it doesn't cure. It helps people, but it doesn't cure them."
This brings us to phase two of Isaacs' cancer-fighting strategy:
Putting prostate cancer cells on a leash, with highly-promised drugs
called angiogenesis inhibitors.
Like Roman soldiers, advancing cancers pave the way before them, laying
down a track of new blood vessels. This guarantees a ready-made
supply of nutrients -- nourishing meals for the road -- which, it
seems, the cancers absolutely cannot do without. Destroy this
infrastructure, cut off the supply line, block these new blood vessels
-- and the cancer cells starve.
Cancer cells make new blood vessels grow by subverting a normal process
involved in wound healing. "Usually, once you become an adult, your
blood supply is pretty stable, and -- except when your body's trying to
repair an injury -- you don't really need new blood vessels," says Isaacs.
"But in order for a cancer to grow, it has to stimulate its host to do
a lot of things for it. A cancer isn't an autonomous machine that can
grow anywhere; it's not like an air fern that just needs sunlight and
water. It's very dependent on its host, and one of the major reasons why
is because it needs vigorous growth of new blood vessels."
This process is called angiogenesis, and drugs to block it, called
angiogenesis inhibitors, already exist. The good thing about these
drugs, says Isaacs, is "that your other blood vessels -- supplying your
heart, lungs, brain and normal tissue -- are already fully developed.
Inhibitors of angiogenesis don't really produce any damage to them. They
would target the blood vessels only in cancerous areas."
Isaacs and colleagues have been working with an angiogenesis inhibitor
called Linomide, which has many qualities of a "dream" drug: It's
inexpensive and already available, it can be given in pill form, it has
low toxicity and hardly any side effects -- and it does a beautiful job of
stalling tumor growth. Best of all, "there's really no way the cancer
cell can become resistant to its requirement for blood vessels." That
would be like a lung cells becoming resistant to oxygen.
"The disadvantage is that it's not something you could take only once
and then never take again," says Isaacs. "The blood vessels are
constantly being stimulated to grow by the tumor, so you'd have to
take this chronically -- like someone with high blood pressure who
takes medication every day." But many men might find this a tiny price
to pay for the potential benefits -- putting a cancer's growth in
slow-motion for years, perhaps even decades. "Say a man has very
limited, micrometastatic disease," says Isaacs, "we know that, untreated,
it might take five or six years for this cancer to produce symptoms.
But an anti-angiogenic medication might be able to prevent this happening
in 20 years. If the man is 60 years old, that may allow him to
not die from prostate cancer. He may still have prostate cancer cells
in his body -- this doesn't eliminate all of them -- but it will
allow him to survive his cancer."
For Men with Extensive Disease, A Molecular Bomb
But an angiogenesis inhibitor won't do enough to combat more advanced
disease. Starting the drug once cancer has become entrenched --
when it starts producing such symptoms as bone pain -- would be like
closing the proverbial barn door after the horse has already
galloped away: Too little, too late. "What these anti-angiogenic
agents do is inhibit the growth of a tumor," Isaacs explains.
"If a man has very extensive disease, they won't cause the tumor
to regress and melt away."
So how to help these men, who need an effective long-term treatment
most of all? This is phase three of Isaacs' research program:
A molecular grenade that only detonates in cells that make PSA.
"We're taking advantage of two attributes of prostate cancer here,"
Isaacs says. "One is that it makes PSA, and the other is that PSA
is an enzyme that can -- like a pair of molecular scissors --
clip protein." PSA recognizes certain strings of amino acids, the
building blocks of protein, and cuts them up. (The specific proteins
are involved in making a sperm-trapping gel, which is part of the semen;
the prostate's main job is to contribute part of the fluid for semen.)
Isaacs and colleagues are designing a drug by genetically doctoring a
potent toxic molecule, hooking it chemically with this protein carrier --
so that's it's activated when PSA goes into its protein-clipping
mode. Then the PSA, recognizing this sequence of proteins that it's
supposed to cut will, in effect, pull the pin on its own grenade:
One clip and boom! Out comes the toxic molecule.
The secret is an unlikely terminator, derived from an innocuous-looking
member of the parsley family. "It's a compound called thapsigargin,
isolated from the thapsia gargancia plant, found in the Mediterranean"
says Isaacs. (He is working in collaboration with Soren B. Christensen.
the medical chemist from the Royal Danish School of Pharmacy who
first isolated, characterized and named thapsigargin.)
For nearly 2,000 years, resin from this plant has been a staple of
Arabian medicine; it's a natural irritant, easily absorbed through
the skin, which can ease the pain of rheumatism. Thapsigargin works by
burrowing its way into a cell and targeting a protein that acts as a
calcium pump: Like someone bailing water out of a leaky rowboat,
this pump keeps calcium from rising above a certain level inside
The most interesting thing here is the calcium, which also happens to be
a key that turns the engine of a genetic process called
programmed cell death; the Greek name for this is apoptosis,
which refers to leaves dropping off a tree. "This gives cells very
specific signals to activate a process of suicide," says Isaacs.
"Normally, calcium is almost 10,000-fold higher outside a cell than
within it. If too much of the calcium gets inside it, it causes the
cell to reprogram itself and activate this suicide pathway." The
effect is like cranking up the gauge on a pressure cooker.
Programmed cell death is certainly not a new concept. It's fundamental
to how babies develop -- the way certain cells in limb buds die, for
instance, so that fingers and toes can form. It's the reason a tadpole
looses its tail and becomes a frog. "If you look at these developing
limb buds (in an embryo), the cells that are going to live are right
next to the cells that are going to die. What could control such a
tightly orchestrated pattern? For a long time, it was assumed that
the microenvironment around the cell basically murdered it -- in
other words, that a bad environment killed the cells. But it's now
clear that the cells that are dying are in a very happy environment:
They've got plenty of nutrients, plenty of oxygen -- they've got
everything that they need to live. But they've been given a signal,
and that signal says: Don't live. Die." And that pathway to death
Now imagine a medieval fortress under siege. The enemy is outside;
but one soldier scales the walls and opens the mighty gates, and
this is all it takes to change the course of battle. By interfering with
the crucial pump, thapsigargin allows that calcium outside the cell to
sneak inside; it reaches too high a level, disrupts the cell,
and activates this pathway of death. "The DNA inside the cell's nucleus
gets all chewed up, becomes degraded to the point of not being useful
for any information. The nucleus itself becomes fragmented, then the cell
becomes fragmented," Says Isaacs. The grand finale is an act of
cannibalism: These little fragments, called apoptotic bodies, are then
consumed by neighboring cells.
"The great thing about this," says Isaacs, "is that the cell has no way
of preventing its own activation of this pathway." Another bonus is that
this death pathway -- unlike many chemotherapeutic drugs -- doesn't require
rapidy dividing cells. It can kill any cell, within 24 to 72 hours.
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