October 31, 2014

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

Volume 1, Winter 2005


In Relentless Pursuit of the “Smart Bomb”

In many ways, it’s the ultimate weapon— cancer-killers delivered at the molecular level, targeting only cancer cells, leaving the rest of the body unscathed. Gene therapy in the laboratory has been remarkably successful, giving scientists a glimpse at what could be. Gene therapy in humans, however, has turned out to be something of a different animal. The basic concept is to sneak new genes into cancer cells that will stop or disrupt their growth, or to use a specific genetic marker inside a cancer cell to trigger a “smart bomb.”

When the cancer-killing bomb is delivered in the form of a virus—viruses are attractive drug-delivery systems, because their one goal is to replicate like mad—the drug has had to contend with the body’s own immune system, which (as it’s supposed to do) recognizes it as an invader, and starts attacking it. Thus, from the moment it hits the bloodstream, the cancer drug-carrying virus—in effect, a Trojan horse—is racing the clock, trying to get to the cancer before the body’s immune system gets to it, and begins creating antibodies.

“We can time the bombs to go off all at once, unleashing a tidal wave—instead of several large splashes—of cancer cell death.”

Also, altered viruses haven’t proven as lethal as the scientists who doctored them had hoped. Because a virus simply exists to replicate—like kudzu in the South—killing cells is its byproduct, not its number one job.

These are some of the challenges facing Ron Rodriguez, M.D., Ph.D., assistant professor of urology, medical oncology, and cellular and molecular medicine. Lesser scientists might give up; Rodriguez, instead, digs in his heels, doubles and redoubles his efforts, and finds new ways around the problems.

Rodriguez has figured out a means of genetically altering these genes to make them more potent, and has engineered the ability to switch them on and off by giving specific medications. One drug, bicalutamide, turns the gene on, and geldanomycin turns it off. This way, he says, “we can time the bombs to go off all at once, unleashing a tidal wave—instead of several large splashes—of cancer cell death.”

Rodriguez has also developed a series of tiny proteins that specifically target and attach themselves to the prostate-specific membrane antigen (PMSA), the outer husk of the prostate cancer cell. By tucking these tiny proteins into the viruses, he will be able to deliver them intravenously—“which means we can target cancer cells throughout the body.”

Rodriguez and colleagues also are exploring other delivery systems. Among the most promising are liposomes. The body doesn’t make antibodies to liposomes, little bubbles of fat that coat DNA. Think of two soap bubbles meeting and sticking together— that’s how a liposome dissolves through a cell’s fatty membrane, and that’s how Rodriguez may be able to bypass the body’s best efforts to fight off even more effective, cancer-killing medications.

“Progress in gene therapy is slow in coming, but it’s being made,” says Patrick C. Walsh, M.D..“I’m thankful we have someone like Ron who is working diligently toward this important end.”

This work was funded in part by Donna and Robert Tompkins.

 

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