October 26, 2014

   A Publication of the James Buchanan Brady
   Urological Institute Johns Hopkins Medical Institutions

Volume VI, Winter 2003

Assassinating Cancer Cells, or Just Stopping Them in their Tracks?


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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