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The challenge isn’t killing cancer cells, says
cancer biologist John Isaacs, Ph.D. “That’s actually not as difficult
as you would imagine.” The real trick, he adds, is figuring out
how to kill cancer cells selectively—so that normal cells, particularly
those in the kidneys, liver, and brain, remain untouched.
Over the last decade or so, Isaacs has come up
with some ingenious ways of doing this. One of them, under Phase
I clinical development, is made from a parsley- like plant called
thapsigargin. Long a staple of medicine in the Mediterranean,
where it’s used to ease the pain of rheumatism, thapsigargin is
a natural irritant, easily absorbed through the skin. It weasels
its way into a cell and starts causing trouble, targeting a protein
that acts as a calcium pump. This pump—like someone baling water
out of a leaky rowboat— keeps calcium from rising above a certain
level inside a cell. Why is this important? Because calcium also
happens to be a key that turns the engine of a genetic process
called programmed cell death, or apoptosis. When too much calcium
comes into a cell, it activates a cell’s self-destruct button.
“It causes the cell to pull the trigger on its own suicide pathway,”
says Isaacs.
Which is great—by activating this pathway, Isaacs
can kill any cell within hours. “The thapsigargin analogues we
have developed were able to cause the death of prostate cancer
cells,” he says. “But they had no specificity.” So how to teach
a drug to discriminate? How to focus the thapsigargin so it leaves
“innocent bystander” cells—normal body cells minding their own
business, causing no harm—alone, but assassinates the deadly prostate
cancer cells that have defied hormone therapy and are headed toward
metastasis?
Two words: Molecular engineering. Isaacs and colleagues
have taken the thapsigargin molecules and reconfigured them, “made
them essentially a smart bomb, so they are unable to get inside
of cells, so they can’t activate this death pathway. We changed
it from being an active drug, when it gets inside a cell, to an
inactive drug that’s kept outside the cell.” They did this by
hooking the thapsigargin to a molecular peptide, a particular
string of amino acids that targets PSA. “PSA is an enzyme that
works like a pair of molecular scissors,” explains Isaacs, “It
can hydrolyze, or clip, certain linkages between molecules.” If
the prodrug were a letter bomb, the PSA would be the knife that
slices it open, and boom—out comes the poison. Interestingly,
although the bomb is activated immediately outside the PSA-making
cell, the prodrug detonates when it moves inside— like the “bunker-busting”
daisy-cutter bombs recently used against terrorists. “The molecular
scissors clip the prodrug, liberate the toxin, and the thapsigargin
molecule is so chemically sticky that it goes right into the cell,
hits the target and kills it.”
| If
the prodrug were a letter bomb, the PSA would be the knife
that slices it open, and boom—out comes the poison. |
Men with prostate cancer have PSA floating around
in their bloodstream; some men with advanced cancer have extremely
high PSA levels, of several thousand nanograms per milliliter,
instead of the usual one- or even two-digit numbers. But the prodrug
would ignore the PSA in the bloodstream, Isaacs explains, “because
it is not chemically active. The PSA is bound to other proteins.”
In other words, the scissors are sheathed, and unable to cut anything
—and the bloodstream becomes a safe delivery system for the prodrug.
“The only enzymatically active PSA is the one right outside the
cells, in either the primary or metastatic sites. Prostate cancers
have very leaky blood vessels; the compound leaks into the fluid
that surrounds these cancer cells. And the nice part here is that
its inherent chemistry makes it want to get into the cell—so we
don’t need to help it get there with any specific energy-dependent
protein or transport machinery.” The prodrug, which Isaacs has
developed in collaboration with the National Cancer Institute,
is undergoing animal toxicity studies required for clinical testing.
Stopping
the Cancer’s Blood Supply
But as promising as thapsigargin is, Isaacs is hedging his bets.
For years, he has also been working on a different strategy— starving
prostate cancer by shutting off its blood supply, or its ability
to create new blood vessels to feed itself. Drugs that do this
are called angiogenesis inhibitors, and Isaacs has been working
with a particular one called Linomide; over the years, he’s developed
“sons of Linomide” that are 100- to 500-fold more potent, with
even fewer side effects, in collaboration with a company called
Active Biotech, Inc. Preclinical studies of the drug’s safety
are under way, and Isaacs anticipates that clinical trials will
begin in a year.
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