DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Novel Tumor Suppressive Role of Phosphodiesterases in Prostate Cancer

Posted June 4, 2021

Qianben Wang, Ph.D., Duke University
Jiaoti Huang, M.D., Ph.D., Duke University
Steven Clinton, M.D., Ph.D., The Ohio State University

Dr. Qianben Wang
Dr. Qianben Wang
Dr. Jiaoti Huang
Dr. Jiaoti Huang
Dr. Steven Clinton
Dr. Steven Clinton

Phosphodiesterase inhibitors (PDEis) are a class of compounds utilized in the treatment of a myriad of conditions, the most common of which is erectile dysfunction. PDE5 inhibitors such as sildenafil (Viagra) are widely used by men at risk of prostate cancer, those on active surveillance, and many men following or during prostate cancer treatment to aid in the recovery of sexual function and quality of life. However, the effects of PDE5 inhibitors on the biology of prostate cancer cells have not been thoroughly investigated, and the impact of their use on prostate cancer risk or progression remains uncertain.

A team led by Drs. Qianben Wang and Jiaoti Huang at Duke University and Dr. Steven Clinton at The Ohio State University studied the effects of PDE5 inhibitors on the behavior of prostate cancer cells from patients, with grant support from an FY15 PCRP Idea Development Award - Parterning PI mechanism. The team discovered that prostate cancer cells are only mildly affected when PDE5 inhibitors are present at concentrations found in patients. Interestingly, those effects are beneficial rather than harmful, and exposure to higher doses of PDE5 inhibitors interferes with the ability of prostate cancer cells to grow, survive, and migrate. Furthermore, they examined the mechanism by which PDE5 inhibition causes these antitumor effects and found that high doses of PDE5 inhibitors strongly activate the cGMP signaling pathway in prostate cancer cells. While it is not practical to expose patients to these higher doses of PDE5 inhibitors, these studies could provide insight for the discovery of novel therapeutic targets in the cGMP pathway.

These findings strongly support the safety of continued PDE5 inhibitor use by both men at risk for prostate cancer and the current prostate cancer patient population. Additionally, these results could provide important clues for the discovery of novel therapeutic strategies that may benefit patients by not just treating their prostate cancer, but also increasing their quality of life.

Publications:

Hankey W, Chen Z, Wang Q. Shaping Chromatin States in Prostate Cancer by Pioneer Transcription Factors. Cancer Res. 2020 Jun 15;80(12):2427-2436. doi: 10.1158/0008-5472.CAN-19-3447. Epub 2020 Feb 24. PMID: 32094298

Hankey W, Sunkel B, Yuan F, He H, Thomas-Ahner JM, Chen Z, Clinton SK, Huang J, Wang Q. Prostate Cancer Cell Phenotypes Remain Stable Following PDE5 Inhibition in the Clinically Relevant Range. Transl Oncol. 2020 Sep;13(9):100797. doi: 10.1016/j.tranon.2020.100797. Epub 2020 May 23. PMID: 32454444

Park JW, Lee JK, Witte ON, Huang J. FOXA2 is a sensitive and specific marker for small cell neuroendocrine carcinoma of the prostate. Mod Pathol. 2017 Sep;30(9):1262-1272. doi: 10.1038/modpathol.2017.44. Epub 2017 Jun 16. PMID: 28621319; PMCID: PMC6330177.

Link:

Novel Tumor Suppressive Role of Phosphodiesterases in Prostate Cancer


Figure
Prostate cancer cell treatment with PDE5 inhibitors, at concentrations found in patients, enhances the accumulation of the small molecule cGMP (represented in red), but does not dramatically change cell biology. Higher-dose PDE5 inhibitor treatment interferes with prostate cancer cell growth, survival and migration. Ongoing studies will investigate the target proteins (represented in green) responsible for these potentially beneficial effects.

Top of Page

Last updated Friday, June 4, 2021