Novel Tumor Suppressive Role of Phosphodiesterases in Prostate Cancer
Abstract
With the 1998 approval of the phosphodiesterase inhibitor (PDEi) Viagra for use in the treatment of erectile dysfunction (ED), the pharmaceutical industry has invested vast resources into the development of an increasing array of similar compounds that disrupt the activity of a large and complex family of biologic enzymes known as phosphodiesterases (PDEs). PDEis have since shown promise as effective therapies for conditions ranging from chronic obstructive pulmonary disease (COPD) to dementia. The most prevalent use for PDEis remains the treatment of ED, and the application of so-called lifestyle drugs such as Viagra, Levitra, and Cialis is only expected to grow as the aging male population places an increasing emphasis on maintaining sexual health. Within the prostate cancer field, ED is recognized as an unfortunate, yet common result of primary prostate cancer therapeutic strategies including radiation and radical prostatectomy (RP), and it is appreciated that the rapid rehabilitation of ED following prostate cancer treatment is essential for restoring future sexual activity. It is within this context that concerns have arisen regarding the deleterious effect of PDEi use on prostate cancer outcomes. A recent study revealed that men given post-RP PDEi treatment were more likely to experience prostate cancer recurrence than men who were not prescribed a PDEi. This controversial observation is supported by a number of recent studies demonstrating that when PDEs are mutated or silenced, prostate cancer cells develop characteristics of aggressive cancer and patients experience poor clinical outcomes. Altogether, these findings suggest that PDEs may have a functional role in the prostate that restricts the growth of malignant cancer cells, and it would therefore be inappropriate to disrupt the activity of these tumor suppressors with PDEi compounds. We believe this notion demands immediate investigation, and in this proposal, we aim to provide the first conclusive evidence that PDEs indeed function as tumor suppressors in prostate cancer. Our work will integrate the expertise of basic scientists, who will clearly define the activity of PDEs in laboratory models of prostate cancer, as well clinicians, who will apply our experimental findings to determine the impact of PDE activity on real-world clinical outcomes. While our initial focus will center on malignant prostate cancer, establishing a tumor suppressive role for PDEs will have tremendous impact throughout the healthcare industry. Immediate implications of our work include the use of PDEs as biomarkers of clinically relevant prostate cancer, aiding in the accuracy with which physicians identify patients in need of treatment. Additionally, this novel concept may lead to near-term moratorium on PDEi use within the prostate cancer setting as a standard means of rehabilitating ED, in order to improve therapeutic cure rates. More broadly, the results of our study may stimulate further investigations that expand our insights to additional forms of cancer and apply these concepts to study the impact of PDEi use on cancer incidence in non-afflicted populations. The pervasive and increasing use of PDEis demands that these issues be resolved without delay to realize an immediate benefit on cancer incidence and outcomes worldwide.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610291
Entities
People
- Qianben Wang
Organizations
- Ohio State University
- United States Army