P52 Activation and Enzalutamide Therapy in Prostate Cancer

There has been a major focus on the androgen receptor AR pathway as the principal therapeutic target for CRPC including recently approved therapies such as next-generation antiandrogen enzalutamide and abiraterone. Despite these advances that provide temporary respite, almost all patients will go on to die from progressive and resistant prostate cancer. Therefore, there is an urgent need to identify resistant pathways that perpetuate disease progression. We provided preliminary data demonstrating that p52 increases AR variant V7 AR-V7 expression and enhances prostate cancer cell resistance to next generation antiandrogen enzalutamide treatment. We hypothesize that overexpression of p52 signaling activates resistance pathways to enzalutamide and co-targeting p52 will overcome treatment resistance. In this project, we will examine the potential mechanisms underlying p52-mediated treatment resistance Aim 1. Aim 2 will validate the efficacy of co-targetingp52 to overcome treatment resistance to enzalutamide. We hope to identify the mechanisms of adaptiveresistant pathways that are responsible for enzalutamide resistance, and provide a rationale for therapeutic co-targeting to overcome enzalutamide resistance