Although second-line antiandrogen therapy (SAT) is the standard of care in men with castration-resistant prostate cancer (CRPC), resistance inevitably occurs. One major proposed mechanism of resistance to SAT involves the emergence of androgen receptor (AR) splice variant-7, AR-V7. Recently, we developed MTX-23 using the principle of proteolysis targeting chimera (PROTAC) to target both AR-V7 and AR-full length (AR-FL). MTX-23 has been designed to simultaneously bind AR's DNA binding domain (DBD) and the Von Hippel–Lindau (VHL) E3 ubiquitin ligase. Immunoblots demonstrated that MTX-23's degradation concentration 50% (DC50) for AR-V7 and AR-FL was 0.37 and 2 μmol/L, respectively. Further studies revealed that MTX-23 inhibited prostate cancer cellular proliferation and increased apoptosis only in androgen-responsive prostate cancer cells. The antiproliferative effect of MTX-23 was partially reversed when either AR-V7 or AR-FL was overexpressed and was completely abrogated when both were overexpressed. To assess the potential therapeutic value of MTX-23, we next generated 12 human prostate cancer cell lines that are resistant to the four FDA-approved SAT agents—abiraterone, enzalutamide, apalutamide, and darolutamide. When resistant cells were treated with MTX-23, decreased cellular proliferation and reduced tumor growth were observed both in vitro and in mice. These results collectively suggest that MTX-23 is a novel PROTAC small molecule that may be effective against SAT-resistant CRPC by degrading both AR-V7 and AR-FL.

Bladder neck contracture (BNC) is a well-recognized complication following robot-assisted radical prostatectomy (RARP) for treatment of localized prostate cancer with a reported incidence of up to 1.4%. In this series, we report our institutional experience and management results. A prospectively collected database of patients who underwent RARP by a single surgeon from 2006 to 2012 was reviewed. Watertight bladder neck to urethral anastomosis was performed over 18-French foley catheter. BNC was diagnosed by flexible cystoscopy in patients who developed symptoms of bladder outlet obstruction. Subsequently, these patients underwent cold knife bladder neck incisions. Patients then followed a strict self regimen of clean intermittent catheterization (CIC). We identify the patient demographics, incidence of BNC, associated risk factors and success of subsequent management. Total of 930 patients who underwent RARP for localized prostate cancer was identified. BNC was identified in 15 patients, 1.6% incidence. Mean patient age and preoperative prostate-specific antigen was 58.8 years old and 7.83 ng/mL (range, 2.5-14.55 ng/mL) respectively. Mean estimated blood loss was 361±193 mL (range, 50-650 mL). Follow-up was mean of 23.4 months. Average time to BNC diagnosis was 5.5 months. In three patients, a foreign body was identified at bladder neck. On multivariate analysis, estimated blood loss was significantly associated with development of BNC. All patients underwent cystoscopy and bladder neck incision with a 3-month CIC regimen. Out of 15 index patients, none had a BNC recurrence over the follow-up period. BNC was identified in 1.6% of patients in our series following RARP. Intraoperative blood loss was a significant risk factor for BNC. In 20% of BNC patients a migrated foreign body was noted at vesicourethral anastomosis. Primary management of patients with BNC following RARP should be bladder neck incision and self CIC regimen.

Introduction: Phosphodiesterase type 5 inhibitors (PDE5Is) are the first-line drugs in the management of erectile dysfunction (ED). However, over the past two decades tremendous efforts have been made to identify new clinical uses of PDE5Is beyond their roles in ED. Areas covered: Basic science articles, clinical trials, reviews, and meta-analysis published between 1996 and 2015 were searched using MEDLINE (PubMed interface) to collect the most relevant and impactful studies from our perspectives as practicing urologists. This review mainly focuses on the level one evidence-based clinical efficacy and drug-related toxicity of oral PDE5Is. In addition, drug discovery, pharmacokinetics and pharmacodynamics, potential use in other diseases, and future directions are discussed. Expert opinion: On-demand PED5Is for the treatment of ED has shifted toward chronic administration in a broad spectrum of conditions that are thought to be associated with endovascular health. Several studies have shown that PDE5Is may play a cardioprotective or neuroprotective role. Further studies are under way to verify beneficial effects of PDE5I in non-urological conditions.