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Purpose: Enzalutamide (ENZ) is a potent androgen receptor (AR) antagonist with activity in castration-resistant prostate cancer (CRPC); however, progression to ENZ-resistant (ENZ-R) CRPC frequently occurs with rising serum PSA levels, implicating AR full-length (AR FL ) or variants (AR-Vs) in disease progression.Experimental Design: To define functional roles of AR FL and AR-Vs in ENZ-R CRPC, we designed 3 antisense oligonucleotides (ASO) targeting exon-1, intron-1, and exon-8 in AR pre-mRNA to knockdown AR FL alone or with AR-Vs, and examined their effects in three CRPC cell lines and patient-derived xenografts.Results: ENZ-R-LNCaP cells express high levels of both AR FL and AR-V7 compared with CRPC-LNCaP; in particular, AR FL levels were approximately 12-fold higher than AR-V7. Both AR FL and AR-V7 are highly expressed in the nuclear fractions of ENZ-RLNCaP cells even in the absence of exogenous androgens. In ENZ-R-LNCaP cells, knockdown of AR FL alone, or AR FL plus AR-Vs, similarly induced apoptosis, suppressed cell growth and ARregulated gene expression, and delayed tumor growth in vivo. In 22Rv1 cells that are inherently ENZ-resistant, knockdown of both AR FL and AR-Vs more potently suppressed cell growth, AR transcriptional activity, and AR-regulated gene expression than knockdown of AR FL alone. Exon-1 AR-ASO also inhibited tumor growth of LTL-313BR patient-derived CRPC xenografts.Conclusions: These data identify the AR as an important driver of ENZ resistance, and while the contributions of AR FL and AR-Vs can vary across cell systems, AR FL is the key driver in the ENZ-R LNCaP model. AR targeting strategies against both AR FL and AR-Vs is a rational approach for AR-dependent CRPC.

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Objective: To search for a biological marker to distinguish low-risk from high-risk bladder cancer indicating disease progression. Methods: The whole genome-wide copy numbers were screened in 18 patients with bladder cancer using array comparative genomic hybridization (CGH) consisting of 4,030 bacterial artificial chromosome clones. Results: Gain of 5p15.33, including TPPP (tubulin polymerization-promoting protein)and ZDHHC11 (zinc finger DHHC domain-containing protein 11) genes, was detected in 5 of 9 (55.6%) high-grade bladder cancers and no (0%; n = 9) low-grade bladder cancer. To confirm the preliminary data, 5p15.33 gain was studied by fluorescence in situhybridization (FISH) in 100 patients, and the results were compared with biological characteristics. In FISH analysis, gain of 5p15.33 was significantly correlated with higher histological grade (p < 0.0001) and advanced pathological stage (p = 0.0284). Tumors with a gain of 5p15.33 had a significantly higher progression-free survival rate than those without (p = 0.0006, log-rank test). Multivariate analysis revealed that gain of 5p15.33 was a predictor for disease progression in bladder cancer (hazard ratio: 1.887, 95% confidence interval: 1.215–2.968, p = 0.0050). Conclusion: These data suggest that gain of 5p15.33 (TPPP and ZDHHC11) may become a potential biomarker identifying high-risk patients with disease progression in bladder cancer.

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