September 20, 2014

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

Volume III, Winter 2007

Turning Back the Clock on Advanced Cancer

When prostate cancer becomes advanced, its cells change. They go from being "well - differentiated," having clear borders, and well-defined shapes, to being more runny — morphing into little, malignant blobs. Over the last decade, scientists have been studying drugs called "differentiating agents" that can help reverse this process — restoring shape and definition to cancer cells, and slowing down their rate of growth.

"In the past, scientists have focused predominantly on short-term treatment with these agents, looking for rapid changes in tumor regression," explains urologist Ronald Rodriguez, M.D., Ph.D., who is also an expert in molecular biology and viral oncology. But short-term studies of these drugs have been disappointing. He believes that giving differentiating agents to a man who already has advanced cancer, and hoping for a quick turnaround, is not the best way to approach these drugs. "Recently, we have discovered that if these agents are given over long periods of time, the effect on tumor progression can be profound," he says.

Even more exciting: Giving the drugs chronically may even take the most hardened, difficult-to-kill cancer cells - the ones called "androgen-independent," which no longer depend on hormones and can't be killed by hormonal therapy - and make them more vulnerable. "This appears to sensitize certain types of androgen-independent cancer cells, converting them back into androgen-dependent cells," says Rodriguez. "These findings may have the most significant impact on men who develop a PSA recurrence after radical prostatectomy." He and colleagues are now working to develop clinical studies based on their most recent data, published in the journal, Cancer Research.

“If these agents are given over
long periods of time, the effect
can be profound.”

Lethal viruses: In 1997, Rodriguez and colleagues were the first to harness a common cold virus, called the adenovirus, as a weapon specifically designed to kill prostate cancer cells. The adenovirus normally kills any cell it invades; the trick of gene therapy was to make this an "oncolytic" virus—to get it to target and invade cancer cells. Working with this virus was one of the toughest challenges Rodriguez has ever wrestled with, but he eventually engineered the adenovirus so that it would only detonate when it came in contact with prostate cells. "This had significant clinical activity when we injected it directly into the prostate of patients who failed radiation therapy," he notes. "But the real need is in men with advanced disease — and for these men, direct injection is not an option." They tried injecting the viruses intravenously, and had to face two enemies — prostate cancer, and the patients' livers. The liver's job is to filter out chemicals that appear harmful. "Despite the fact that greater than 99 percent of the viruses injected this way were sequestered in the liver, we were still able to demonstrate clinical activity." This work was published recently in Molecular Therapy.

To overcome this obstacle, they worked to make the virus — what little of it could make it past the liver — even more potent. Rodriguez and colleagues also have developed a means to bypass the liver, and "get much more of the virus to the prostate cancer cells." Those efforts are being led by scientist Shawn Lupold, Ph.D. Eventually, Rodriguez believes, "with these new developments, we will be able to have a significant impact on the patients with the greatest need — men with advanced prostate cancer.”

 

 

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