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Sylvester Researchers Show Nitric Oxide Suppresses Drug-Resistant Prostate Cancer

Researchers at Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine have shown in animal models that S-nitrosoglutathione (GSNO), a compound that increases nitric oxide (NO) levels, suppresses castration-resistant prostate cancer and has a major impact on tumor microenvironments. The discovery could lead to new therapies for prostate cancer patients with few options. The study was published in the journal Proceedings of the National Academy of Sciences.

From left, Himanshu Arora, Ph.D., with Ranjith Ramasamy, M.D.

“By using the nitric oxide donor GSNO, we increased nitric oxide levels and suppressed the growth of this particular type of prostate cancer,” said Ranjith Ramasamy, M.D., assistant professor in the Department of Urology and senior author of the manuscript.

“But even more important, the tumors did not develop further resistance that commonly occurs with most therapies currently available for prostate cancer,” said Himanshu Arora, Ph.D., a researcher in the Department of Urology and first author of the manuscript.

Men with prostate cancer are often given androgen deprivation therapy, which blocks hormones that drive cancer growth. Unfortunately, tumors evolve over time, increasing the number of androgen receptors and adopting other mechanisms to resist this treatment.

Fortunately, patients have options. Drugs like enzalutamide and abiraterone can extend remission, but again, many cancers ultimately learn to resist these therapies, and men eventually run out of choices.

To better understand the role nitric oxide plays in resistant prostate cancer, the researchers tested whether GSNO affects human tumor xenografts in animal models. They chose a prostate cancer subtype, called ARV7, which is resistant to both enzalutamide and abiraterone.

The study found the compound suppressed these tumors and continued to suppress them with no signs of resistance. The increased NO helped neutralize the tumor microenvironment — the complex, inflammatory shell around which tumors grow. Specifically, GSNO reduced levels of tumor-associated macrophages, immune cells that cancers co-opt into their microenvironment.

“We were very excited to discover that a drug like GSNO, which increases the activity of nitric oxide, suppressed the growth of this type of prostate cancer,” said Joshua M. Hare, M.D., the Louis Lemberg Professor of Medicine, director of the Interdisciplinary Stem Cell Institute, and an expert in nitric oxide signaling. “Our findings regarding the long-term suppression of the tumor growth open important possibilities for developing a new class of drugs for prostate cancer.”

These findings could have a significant clinical impact in a relatively short time. GSNO is already in clinical trials for asthma and pulmonary fibrosis. With additional work, the compound could be retasked against castration-resistant prostate cancer, as well as other tumor types.

“This discovery should reach its logical conclusion of being tested in future clinical trials in men with castration-resistant prostate cancer who are non-responsive to both abiraterone and enzalutamide” said Dipen J. Parekh, M.D., professor and chair in the Department of Urology, director of robotic surgery and chief clinical officer of UHealth.

Tags: GSNO, nitric oxide, prostate cancer