Castration-recurrent prostate cancer CR-CaP represents the greatest cause of CaP-associated mortality due to its resistance to standardchemo- and radiotherapies that are efficacious against primary, androgen sensitive AS-CaP. CR-CaP progresses to metastatic disease inlocal lymph nodes and bone in the absence of serum androgen levels. Two recently FDA-approved drugs, abiraterone ABI andenzalutamide ENZ, have shown clinical efficacy against CR-CaP, yet drug resistance readily occurs within months of treatment, severelylimiting clinical benefit. This validates these drugs and their targets in CR-CaP, however, knowledge regarding the mechanism underlyingABI- and ENZ-resistance will greatly benefit CR-CaP patients by producing better long-term efficacy of these drugs as well as nextgeneration versions. The current proposal aims at directly dissecting the molecular mechanism underlying ABI and ENZ resistance in CRCaP.This is based on recent data showing that a shortened variant of the androgen receptor AR protein, called AR-V, is directlyresponsible for malignancy of CR-CaP, and moreover, that ENZ or ABI treatment actually enhances production of AR-V, leading to moredrug resistance. We plan to isolate the AR gene sequence responsible for enhancing AR-V production using a novel molecular genetictechnique, and then to identify the enhancer-binding proteins that drive enhancer activity, with the long-term aim to prevent ENZABIresistance by interrupting this interaction with small molecule inhibitors. Thus, this project is very timely and novel, and its findings will have amajor benefit to CR-CaP patients by identifying pathways to enhance ENZ and ABI targets.