PDE5 Inhibitor (Sildenafil) for Ameliorating Androgen Deprivation Therapy (ADT)-Induced Cardiotoxicity
Abstract
Rationale and Objective: Androgen deprivation therapy (ADT) is the cornerstone for metastatic prostate cancer (PCa). ADT is achieved either by surgical or by chemical castration. Since 1990, the majority of locally advanced and metastatic PCa patients have been treated with GnRH agonists, such as leuprorelin (Lupron, Lupron depot, Eligard, and Viadur) and goserelin (Zoladex). Although initially PCa responds to ADT, in a majority of cases, tumors relapse and develop into castration-resistant PCa, which has a poor prognosis. There is also increasing evidence that the use of Lupron and Zoladex is associated with increased risk for cardiovascular events among PCa patients. However, currently no experimental study has reported the detrimental effect of GnRH agonist in the heart, and no novel therapeutic strategy has been developed or even conceptualized to prevent GnRH agonist-induced cardiac dysfunction. The underlying mechanism and association between GnRH agonists and cardiovascular events is not clear. We have discovered the cardio-protective effects of the erectile dysfunction drug, sildenafil citrate (Viagra and Revatio), against injuries that result from loss of blood flow (ischemia), restoration of blood flow (reperfusin), heart failure, and cardiomyopathy resulting from chemotherapy (doxorubicin). In our preliminary studies, we also observed the protective effect of sildenafil on cardiomyocyte death induced by GnRH agonists. Our objective is to determine the protective role and mechanisms of sildenafil against cardiotoxicity caused by GnRH agonists (Lupron and Zoladex), and we propose three specific aims. Specific Aims: Aim 1. Investigate the therapeutic potential of a PDE5 inhibitor, sildenafil, on ADT (GnRH agonists)-induced cardiovascular dysfunction (in vitro and in vivo). Aim 2. Determine the therapeutic benefits of sildenafil in improving the GnRH agonists-induced cardiotoxicity in a murine PCa progression model (GEMMs). Aim 3. Elucidate the molecular mechanisms of sildenafil in ADT-induced cardiovascular events. Clinical Applicability and Outcome: The project proposes novel therapeutic interventions to improve the quality of life for millions of PCa survivors (especially patients who received ADT). The outcome of the project is immediate because sildenafil is Food and Drug Administration-approved for the treatment of erectile dysfunction and hypertension. The results of this study will directly lead to the start of a phase-3 clinical trial for ADT-induced cardiotoxicity. To date, there is no known potential risk associated with sildenafil use in patients. Emerging research also suggests that cardiovascular complications related to classical metabolic syndrome differs from ADT-induced metabolic syndrome. Understanding the underlying mechanism of ADT (GnRH) agonists-induced cardiotoxicity will help establish biomarker(s) that can help identify the patients who are risk of developing ADT-induced cardiovascular complications. Patients Likely to Benefit from this Study: The PCa patients who are undergoing or have previously received ADT will directly benefit from this study. According to American Cancer Society 2016 statistics, there are 3.3 million PCa survivors, and these numbers are predicted to increase to 4.5 million in 2025, or about 54% of male cancer survivors. Epidemiological studies estimate that ~50% of patients undergo ADT at some point of their treatment course, and that at least 20-30% of those patients develop the risk of cardiovascular disease, particularly with drugs such as Lupron and Zoladex. Further, the SEER database and Swedish cancer registry estimate cardiovascular disease as the single highest cause of death in PCa patients. Considering this, it is expected that at least 1 million PCa survivors are living with ADT treatment-induced cardiovascular risk and complications at any given time. Because sildenafil has been shown to be potent and safe, completion of
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810309
Entities
People
- Rakesh C Kukreja
Organizations
- United States Army
- Virginia Commonwealth University