The primary male sex hormone testosterone regulates development of male reproductive tissues. Testosterone binds to the androgen receptor (AR) triggering a cascade of signals that ultimately cues cells to grow and divide. In a majority of prostate cancers, ARlevels are elevated which drives formation of prostate cancer tumors. Anti-androgen drugs have been developed to inhibit this mechanism. However, in some prostate cancers the AR can be suppressed, making anti-androgen therapy ineffective. These patients are found to be more resistant to all therapies. Prostate-specific membrane antigen (PSMA) is a transmembrane protein that is over-expressed in a majority of prostate tumors as well as in metastatic lesions. Imaging prostate cancer using SMA is a very useful approach. However, a few clinical reports suggest that PSMA-targeted imaging is not able to detect some aggressive tumors. With Ride for Dad funding in 2018 we have provided convincing data demonstrating that indeed PSMA is not a reliable marker for some of the patients, and we have begun to propose more rigorous options for these patients. This proposal will determine how PSMAis suppressed and it will be the first to investigate the alternative options for PSMA-imaging for some of the most aggressive prostate cancers.