An imaging agent to detect androgen receptor and its active splice variants in prostate cancer
Yusuke Imamura, Amy H. Tien, Jinhe Pan, Jacky K. Leung, Carmen A. Banuelos, Kunzhong Jian, Jun Wang, Nasrin R. Mawji, Javier Garcia Fernandez, Kuo-Shyan Lin, Raymond J. Andersen, Marianne D. Sadar
Yusuke Imamura, Amy H. Tien, Jinhe Pan, Jacky K. Leung, Carmen A. Banuelos, Kunzhong Jian, Jun Wang, Nasrin R. Mawji, Javier Garcia Fernandez, Kuo-Shyan Lin, Raymond J. Andersen, Marianne D. Sadar
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Resource and Technical Advance Oncology

An imaging agent to detect androgen receptor and its active splice variants in prostate cancer

Abstract

Constitutively active splice variants of androgen receptor (AR-Vs) lacking ligand-binding domain (LBD) are a mechanism of resistance to androgen receptor LBD–targeted (AR LBD–targeted) therapies for metastatic castration-resistant prostate cancer (CRPC). There is a strong unmet clinical need to identify prostate cancer patients with AR-V–positive lesions to determine whether they will benefit from further AR LBD–targeting therapies or should receive taxanes or investigational drugs like EPI-506 or galeterone. Both EPI-506 (NCT02606123) and galeterone (NCT02438007) are in clinical trials and are proposed to have efficacy against lesions that are positive for AR-Vs. AR activation function-1 (AF-1) is common to the N-terminal domains of full-length AR and AR-Vs. Here, we provide proof of concept for developing imaging compounds that directly bind AR AF-1 to detect both AR-Vs and full-length AR. 123I-EPI-002 had specific binding to AR AF-1, which enabled direct visualization of CRPC xenografts that express full-length AR and AR-Vs. Our findings highlight the potential of 123I-EPI-002 as an imaging agent for the detection of full-length AR and AR-Vs in CRPC.

Authors

Yusuke Imamura, Amy H. Tien, Jinhe Pan, Jacky K. Leung, Carmen A. Banuelos, Kunzhong Jian, Jun Wang, Nasrin R. Mawji, Javier Garcia Fernandez, Kuo-Shyan Lin, Raymond J. Andersen, Marianne D. Sadar

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Figure 5

123I-EPI-002 shows uptake in xenografts that endogenously express ARs.

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123I-EPI-002 shows uptake in xenografts that endogenously express ARs. ...
(A) Tumor-blood and tumor-muscle ratios of LNCaP95 xenografts. n = 3–8 at each time point. Data are shown as mean ± SEM. (B) Effects of EPI-002 cotreatment on 123I-EPI-002 accumulation in blood, muscle, LNCaP95, and PC3 xenografts (1-hour treatment). The accumulation of 123I-EPI-002 in LNCaP95 xenografts was significantly decreased by blocking with EPI-002. n = 3–7. Data represent mean ± SD. ***P < 0.001. One-way ANOVA Dunnett’s multiple comparison test was utilized. (C) Axial and coronal micro-SPECT/CT images of castrated NOD/SCID mice bearing LNCaP95 (arrow) and PC3 (arrowhead) xenografts 2 hours after coinjection of 123I-EPI-002 with (Block) or without excess dose of EPI-002 (Unblock). The images are scaled to the same threshold. Color scale indicates the level of radioactivity. n = 2. (D) H&E staining and immunohistochemistry (AR) of representative sections of formalin-fixed, paraffin-embedded LNCaP95 and PC3 xenografts with lower magnification. Xenografts were extracted approximately 6 weeks after subcutaneous injection of LNCaP95 and PC3 cell lines. The histological analysis demonstrated that LNCaP95 cells that expressed the AR formed a largely concentrated tumor, which resulted in a necrotic center. Scale bar: 40 μm. (E) Protein expression obtained from LNCaP95 and PC3 xenografts. Four xenografts from each cell line are shown. Western blot analysis of LNCaP95 xenografts showing both full-length AR and AR-V7 expression, both of which were negative in PC3 xenografts. β-Actin is shown as a protein loading control. Refer to full and uncut gel images in Supplemental Materials.