July 28, 2014

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

Volume II, Autum 2005

Gene Warfare: The Latest from the Front

For the last several years, Ron Rodriguez, M.D., Ph.D., has tried to do what nobody else has ever done — kill prostate cancer with gene therapy. And there’s a reason nobody’s ever done it — because it’s really hard. Rodriguez assistant professor of urology, medical oncology, cellular and molecular medicine, and viral oncology, and director of the Urology residency program, has labored valiantly over several Herculean projects, each taking aim at prostate cancer in a unique way.

One approach involves changing a common virus, called the adenovirus, into a cancer-killing machine. Rodriguez and colleagues have developed several generationsof these adenoviral gene therapy drugs, each better than the last. “We are generating new technology to allow adenoviruses to attach themselves only to prostate cancer cells,”Rodriguez reports. “This has never been accomplished before, and is the most ambitious project taken by a gene therapy group to date. We have overcome some oft he initial obstacles, which at one point were thought to be insurmountable.” One breakthrough came in the form of new technologies that allowed the scientists to rebuild genes by exchanging bits of DNA, like shuffling a deck of cards. Another breakthrough was the discovery of certain peptides that specifically bind to PSMA, prostate-membrane specific antigen, a protein that is made on the surface of prostate cells. “We have published the new peptides and are in the process of incorporating them into the adenoviruses,” he says. “It has been far more complicated than we had originally anticipated. However, we have been able to identify each obstacle and systematically engineer a solution to the problem. We are gaining confidence that the approach will pay off in the long run.”

All of these challenges have produced a nice bonus, Rodriguez notes. “The tools that we needed to perform this genetic engineering work did not exist.” So Rodriguez and colleagues had to develop them — a series of powerful methods to perform complex viral manipulations. The good news here is that these same tools can now be applied to othe rresearch problems that were once thought unapproachable — which Rodriguez hopes to do, with more funding.

Another molecular approach involves drugs called differentiating agents. Normally, cells appear well differentiated — they have distinct, clearly defined borders, and their growth is fairly slow and orderly. The opposite of this is cells that are poorly differentiated. Highly malignant and aggressive, these are the cells that are given high Gleason grades by a pathologist (Gleason 8, 9, or 10). In physical appearance they are not well defined; instead, they seem to melt together. The good news is that it’s possible, at least in the laboratory, to slow down this growth, and to make poorly differentiated cells more distinct — to make them less dangerous, and more like normal cells.

“In the past, clinical trials devoted to this approach have not worked,” says Rodriguez. But in recent research, he and colleagues have found that the best way to turn a cell away from cancer and back toward normal

The good news is that it’s possible, at least in the laboratory, to slow down the growth of the most aggressive cancer cells — to make them less dangerous,and more like normal cells.

is to do it gradually, and continually. “We’ve found that the optimal activity requires prolonged, chronic exposure to the drug —not short-term exposure, as given in previous clinical trials.” Rodriguez believes that administering a differentiating agent continuously — and starting well before any symptoms of advanced cancer, most likely at the first rise in PSA after a man’s initial treatment — will slow the progression of the cancer cells significantly. “The hope is that such an approach would turn a terminal disease into a manageable chronic illness, like HIV.”

 

 

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