Unlocking Prostate Cancer Treatment: Targeting the Androgen Receptor with LNA Antisense Oligonucleotides

Androgen-deprivation therapies are the primary treatment for prostate cancer, but many patients eventually develop castration-resistant disease. This resistance is associated with the continued reliance on a functional androgen receptor (AR), suggesting that targeting AR expression could be a new treatment approach. A novel locked nucleic acid (LNA)-based antisense oligonucleotide (ASO), EZN-4176, has been developed to silence AR and inhibit tumor growth.

The efficacy of EZN-4176 was assessed in AR-positive (LNCaP, 22RV1) and AR-negative (PC3) cancer cell lines. The ASO induced significant downregulation of AR mRNA and protein, leading to inhibited cell growth and increased caspase 3/7 activity. The reduction in prostate-specific antigen (PSA) levels further indicated the compound's biological effects. Notably, these effects were specific to EZN-4176, as a scrambled LNA-ASO did not replicate these results, and EZN-4176 did not affect AR-negative cells.

In vivo studies demonstrated that EZN-4176 administration resulted in a dose-dependent reduction of AR mRNA in the liver and significant inhibition of AR, PSA, and TMPRSS2 mRNA in tumor xenografts. The compound also induced substantial tumor growth inhibition in CWR22 tumor xenografts, comparable to high-dose bicalutamide treatment. The specificity of EZN-4176 was confirmed, as no significant effects were observed with the scrambled LNA-ASO or in PC3 xenograft models. Additionally, EZN-4176 was shown to localize in subcutaneous tumor xenografts using an imaging system.

The findings indicate that EZN-4176 is a potent LNA-based ASO that modulates the AR target and inhibits tumor growth in vivo, presenting a potential new strategy for the treatment of advanced prostate cancer.