Experimental Therapies Show Promise
Ron Rodriguez with research specialist Wasim H. Chowdhury: Their work runs the gamut
from genetherapy to work with viruses, to fi nding new uses for drugs designed to treat
other problems, to immunotherapy and cryoablation (freezing the prostate)
Of all the labs at the Brady doing impressive research, the one that may be hardest to sum up easily belongs to Ron Rodriguez, M.D., Ph.D., the R. Christian B. Evensen Scholar.
That's because Rodriguez is developing experimental therapies for prostate cancer, and his investigations run the gamut from gene therapy to work with viruses, to fi nding new uses for drugs designed to treat other problems, to immunotherapy and cryoablation (freezing the prostate).
The virus seeks out only prostate
cancer cells, and then gives them
a lethal cold.
New life for an old anti-seizure drug:
Rodriguez and colleagues have found that valproic acid, a drug that has been used to treat epilepsy, can slow down the progression of prostate cancer. It appears to work by inhibiting a chemical called histone deacetylase, and this, in turn, causes the cancer to become less aggressive. "We are now actively conducting a one-year clinical trial," in which patients will be randomly assigned to take either this drug or the placebo, says Rodriguez. After one year, those in the placebo group have the option to "cross over" to the valproic acid group. "We believe this drug may have the potential to slow down the progression of prostate cancer signifi cantly," he continues. "In a cancer which already tends to grow slowly, this may be particularly benefi cial." Men are eligible for this trial if they have a PSA greater than 1 after a radical prostatectomy; if they have had no previous hormonal therapy; and if their PSA doubling time is less than 10 months.
Immunotherapy and freezing cancer: In a separate clinical trial, Rodriguez and colleagues are hoping that the combination of cryoablation — killing cancer by freezing the tissue — and immune system stimulation will generate an anti-tumor immune response throughout the whole body. This trial is intended for men with advanced prostate cancer, with at least one area of cancer available for cryoablation, and at least one other site of disease that shows up on an X-ray or other image. "We will perform cryoablation at the primary site of cancer, and then give intravenously a low dose of an immune-boosting drug called cyclophosphamide," Rodriguez notes. Patients will be followed for two years, with imaging and PSA done every three months.
Using viruses to kill cancer: Rodriguez and colleagues have discovered that a common virus, called an adenovirus — changed slightly so that it seeks out only prostate cancer cells, and then gives them a lethal cold — can be combined nicely with highdose radiation therapy.
One challenge fi ghting advanced
prostate cancer is simply being
able to reach it all.
"This combination creates what we call a synergistic cell kill," Rodriguez explains. "The high-dose radiation causes the viruses to replicate more effectively in prostate cells, and this results in more effective killing of the cancer." Rodriguez's lab has been working on this idea for years; in earlier incarnations, the viruses required androgens (male hormones) in order to function properly. "However, the patients with the highest need, men with high-grade cancers, are typically treated with hormone therapy, and this made our viruses ineffective." To fi x this, "we discovered a way of altering our viruses so that treatment with nonsteroidal antiandrogens like casodex can activate them, and cause a synergy of prostate cancer cell death." The scientists are currently conducting preclinical studies of these new viruses, "working out models that we intend to bring to the clinic." Rodriguez anticipates that this approach will be combined with high-dose brachytherapy.
When cancer is contained within
the prostate, it's much easier to
cure; doctors know exactly where
it is. But doctors treating advanced
cancer don't have this luxury.
Gene therapy: One of the challenges of fi ghting advanced prostate cancer is simply being able to reach it all. When cancer is contained within the prostate, it's much easier to cure; doctors know exactly where it is. But doctors treating advanced cancer don't have this luxury. Thus, the best way to make sure a treatment reaches stray prostate cancer cells throughout the body is an intravenous approach — ideally, one that goes everywhere, but only affects prostate cancer cells. Rodriguez and colleagues have developed a new technology, using a particular gene on an adenovirus called the fi ber gene, and specifi cally targeting it to a molecule on the surface of prostate cancer cells, called the PSMA molecule. This in itself is a spectacular feat of genetic engineering; many scientists have attempted it, and Rodriguez's lab is the fi rst to fi gure it out. "Everything appears to be in place for us to succeed," says Rodriguez, "although we expect it will be an arduous process. We are nonetheless committed to fi nding a way to get our highly effective viral missiles to their intended target, and believe that once we have refi ned this targeting process, we will be able to affect diffuse disease in a major way."