Human Oncology and Pathogenesis Program, Department of Radiology, Division of Urology, Molecular Pharmacology and Chemistry, Nuclear Medicine Service, and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
Despite encouraging clinical results with next generation drugs (MDV3100 and abiraterone) that inhibit androgen receptor (AR) signaling in patients with castration-resistant prostate cancer (CRPC), responses are variable and short-lived. There is an urgent need to understand the basis of resistance to optimize their future use. We reasoned that a radiopharmaceutical that measures intratumoral changes in AR signaling could substantially improve our understanding of AR pathway directed therapies. Expanding on previous observations, we first show that prostate-specific membrane antigen (PSMA) is repressed by androgen treatment in multiple models of AR-positive prostate cancer in an AR-dependent manner. Conversely, antiandrogens up-regulate PSMA expression. These expression changes, including increased PSMA expression in response to treatment with the antiandrogen MDV3100, can be quantitatively measured in vivo in human prostate cancer xenograft models through PET imaging with a fully humanized, radiolabeled antibody to PSMA, (64)Cu-J591. Collectively, these results establish that relative changes in PSMA expression levels can be quantitatively measured using a human-ready imaging reagent and could serve as a biomarker of AR signaling to noninvasively evaluate AR activity in patients with CRPC.
Evans MJ, Smith-Jones PM, Wongvipat J, Navarro V, Kim S, Bander NH, Larson SM, Sawyers CL. Are you the author?
Reference: Proc Natl Acad Sci U S A. 2011 May 23. Epub ahead of print.