sitagliptin-phosphate and Prostatic-Neoplasms--Castration-Resistant

The standard treatment for metastatic prostate cancer, androgen deprivation therapy (ADT), is designed to suppress androgen receptor (AR) activity. However, men invariably progress to castration-resistant prostate cancer (CRPC), and AR reactivation contributes to progression in most cases. To identify mechanisms that may drive CRPC, we examined a VCaP prostate cancer xenograft model as tumors progressed from initial androgen sensitivity prior to castration to castration resistance and then on to relapse after combined therapy with further AR-targeted drugs (abiraterone plus enzalutamide). AR activity persisted in castration-resistant and abiraterone/enzalutamide-resistant xenografts and was associated with increased expression of the AR gene and the AR-V7 splice variant. We then assessed expression of individual AR-regulated genes to identify those that persisted, thereby contributing to tumor growth, versus those that decreased and may therefore exhibit tumor suppressor activities. The most significantly decreased AR target gene was dipeptidyl peptidase 4

Topics: Alternative Splicing; Androgen Antagonists; Androstenes; Animals; Benzamides; Cell Line, Tumor; Dipeptidyl Peptidase 4; Disease Progression; Down-Regulation; Drug Resistance, Neoplasm; Epigenesis, Genetic; Gene Expression Profiling; Humans; Male; Mice; Mice, SCID; Neoplasm Recurrence, Local; Neoplasm Transplantation; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; RNA, Small Interfering; Signal Transduction; Sitagliptin Phosphate