Abstract IA22: Molecular Imaging of androgen receptor signalling in CRPC

Abstract

Abstract Androgen receptor (AR) plays a key role in development of castrate-resistant prostate cancer (CRPC), the lethal form of the disease. For this reason we have developed Molecular Imaging (MI) methods to study AR, both in laboratory and clinic. For this work we have used a radiotracer that is highly specific for AR, a flourine-18 analog of dihydrotestoterone, (FDHT) the most abundant androgen at the tissue level in human cancers. In the laboratory for example, we have used FDHT to document AR binding of novel drugs and to determine their relative affinity and the number of AR receptor sites in human prostate cancer cell lines and xenografts. In the clinic we have imaged patients with CRPC to determine the impact of therapies on AR expression. During the course of this work we have developed quantitative kinetic models based on PET imaging and have shown the FDHT binding and uptake into cancers is AR dependent, and that the metabolites of FDHT do not bind appreciably to AR. We have compared FDHT and FDG in CRPC patients and have determined that there are an average of 17 tumors per patient (n=107), and the 90% of metabolically active tumors for FDG or FDHT express AR, but that there is a group of lesions that do not but are detected by metabolism of FDG. We have shown that drugs which target AR displace FDHT completely when used in full pharmacologic doses. So far the data is consistent with the view that this type of displacement is a necessary condition for tumor response, but clearly some patients whose AR binding is completely blocked have lesions which continue to progress through unknown mechanisms. We believe that molecular imaging using antibodies labeled with PET emitters will add greatly to our knowledge about CRPC, and studies in man with 89Zr-DFO J591, and antibody targeting PSMA are just beginning. The impact of AR signaling on PSMA expression has been shown in the laboratory to be down regulation, and we intend to explore the use of antibodies to provide a pharmacodynamic biomarker of AR signaling in man during therapy with AR blockers in the clinic. Citation Format: Steven M. Larson, Joe Fox, Michael Morris, Michael Evans, Jason Lewis, John Humm, Charles L. Sawyers, Howard I. Scher. Molecular Imaging of androgen receptor signaling in CRPC [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr IA22.