Abstract 354: Monitor androgen blockade therapy with functional androgen receptor reporting system

Abstract Hormonal manipulation remains the first line treatment for advanced prostate cancer. It includes surgical and medical means of androgen deprivation and androgen receptor (AR) blockade therapies. However, the majority of patients will develop castration resistant prostate cancer, often with metastasis that accounts for the lethality of this disease. Therefore, a reliable imaging modality capable of active surveillance of tumor recurrence and/or new incidence of metastasis would greatly benefit the timing and decision-making in adopting second line therapies. To this end, we recently constructed a prostate specific yet androgen independent promoter system, namely PSES-TSTA (Prostate Specific Enhancer Sequence coupled with Two-Step Transcriptional Amplification). We used this system to drive PET and optical imaging reporters and successfully visualized subcutaneous tumor and intra-tibial metastasis in castrated mice. The androgen independency of PSES-TSTA, which secured viability of this imaging approach when only castrated level of androgen is available, is attributed to the composition of the chimeric PSES sequence - an androgen inducible element derived from the prostate specific antigen (PSA) gene promoter and an androgen suppressible element from the prostate specific membrane antigen gene enhancer (PSME). Another challenge faced by patients after hormonal ablation therapy is the need for effective second-line therapies. Interestingly, a growing body of evidence points out that even at castration resistant stage, AR remains active and most prostate cancer still rely on AR signaling axis for proliferation and survival. Accordingly, much effort has been devoted to the development of second generation anti-androgen agents. Therefore, it would be greatly beneficial to establish a practical and reliable reporting system that reflects the functional status of the androgen-AR axis so that the efficacy of such new drugs can be monitored at the molecular level. Inspired by previous results, we separated the two components of PSES and generated two imaging reporters: PSA-driven Firefly Luciferase (PSA-FL) and PSME-driven Renilla Luciferase (PSME-RL). Based on their respective response to androgen signaling, we anticipated that the PSA-FL signal will decrease while the PSME-RL signal will increase in the face of an effective anti-androgen therapy. Indeed, we observed such pattern of reporter gene expression in multiple prostate cancer cell lines. Importantly, this system is able to differentiate the potency and efficacy between the first generation and the more potent second generation AR antagonists. Moreover, the simultaneous application of the PSME- and PSA-driven reporter system is advantageous over the single PSA promoter-based reporter in that it rules out the effect of tumor mass reduction on the readout because both up- and down-regulation of gene expression are being assessed and imaged. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 354. doi:1538-7445.AM2012-354