Creative, Never Done Before, Cutting Edge: All in a Day’s Work

Ron Rodriguez, M.D., Ph.D., the R. Christian B. Evensen Scholar, and Shawn Lupold, Ph.D., the Phyllis and Brian L. Harvey Scholar, are combining the forces of their labs and creativity to pursue prostate cancer from multiple fronts. Here’s some of what they have accomplished recently:

Giving cancer a lethal cold:
In work published in Cancer Research, Lupold, Rodriguez, and post doctoral fellow Ping Wu have managed in a few years what others have been trying to do for a decade. It’s called “viral retargeting.” In this case, they used the adenovirus, a pesky bug that produces common cold symptoms. An adenovirus naturally attacks epithelial cells, which are in the tissue that lines structures throughout the body (this makes sense, that a virus that makes your nose run would attack the membrane in the nostrils, and similar tissue elsewhere). The virus attaches to specific receptors on epithelial cells, by means of a fiber protein that lives on its surface (think of Spiderman shooting out sticky string). Using a novel adenovirus-library approach, Lupold and Rodriguez screened millions of slightly-modified viruses to identify one that, instead of being drawn to all epithelial cells, specifically targets PSMA (prostatespecific membrane antigen), found only on the surface of prostate cells.

“This opens the road to developing better treatments for prostate cancer,” says Lupold, “which can be given intravenously, without losing more than 99 percent of the virus to the liver and immune system; this has been a big problem in the past.”

A virus/hormonal therapy/radiation combo:
In separate work, Rodriguez and Lupold have engineered a virus to kill prostate cancer cells when given with an oral anti-androgen medication. “To our the virus in a way that would activate the immune system against the tumor, and this may help prevent early spread of the disease.”

Clinical trials:
Two clinical trials are under way with treatments the Rodriguez lab has developed. One uses valproic acid, an anti-seizure drug that has been around for many years. The drug inhibits a chemical called histone deacetylase, and this slows the growth of prostate cancer. The scientists believe it can help slow down the progression of prostate cancer in men whose cancer has returned after radical prostatectomy. The other trial involves another fusion of treatments, cryotherapy plus immunotherapy. Cryotherapy, or cryoablation, involves freezing the prostate. As a treatment by itself, it has not been shown to cure advanced prostate cancer. However, when an immune-boosting drug called cyclophosphamide is given alongside, it can help strengthen the body’s ability to fight the cancer. Rodriguez and Lupold envision adding several other immune-boosters to the approach, “with the goal of ultimately reversing established metastatic disease,” says Rodriguez. “In our animal models, such multi-armed combinations have been able to reverse metastatic disease in a substantial proportion of our experiments.”

Molecular imaging:
With that useful antigen, PSMA, as a target, the scientists are working with neuroradiologist Martin Pomper, M.D., Ph.D., (himself a previous recipient of a Walsh Fund award). “We are developing an optical agent that can be given intravenously the day before radical prostatectomy, and then imaged in real time during robotic prostatectomy,” says Lupold. “This may enable robotic surgeons to actually see the cancer at the edge of the resection during an operation, minimizing the likelihood of leaving any cancer behind.”


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