Abstract 4212: Inhibition of mouse PTEN-deficient prostate cancer with next generation antisense oligonucleotide targeting the androgen receptor
Authors: De Velasco Marco A. , Kura Yurie , Ando Naomi , Fukushima Emiko , Davies Barry R. , Campbell Hayley , Hatanaka Yuji , Yamamoto Yutaka , Shimizu Nobutaka , Nozawa Masahiro , Yoshimura Kazuhiro , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: August 2015

Resistance to androgen deprivation therapies is characterized by the persistent activation of the androgen receptor (AR). Traditional approaches for the development of novel androgen deprivation therapies have focused on inhibition of AR activity by blocking the production or binding of androgens to the AR. These novel treatment strategies have shown improvements, however, patients still develop castration-resistant disease. Continued AR activity in castration-resistant prostate cancer (CRPC) may be the result of ligand dependent or ligand independent mechanisms. Antisense oligonucleotides (ASO) have the ability to block specific genes inhibiting the associated proteins thus providing an alternate treatment strategy for CRPC. Here, we investigated the in vivo antitumor effects of a generation 2.5 ASO targeting the mouse AR in a PTEN-deficient mouse model of prostate cancer. Pharmacodynamic analysis demonstrated strong inhibition of target RNA by the AR-ASO in prostate tumor tissues. The AR-ASO also exhibited strong suppression of AR protein levels in prostate tumors as demonstrated by western blot analysis. Immunohistochemical analysis confirmed reduced levels of AR expression and transcriptional activity in tumor tissue. Furthermore, AR was also inhibited in normal tissues of the accessory sex glands. The treatment efficacy of the AR-ASO was evaluated in pharmacological intervention trials in mice with castration-naïve prostate cancer (CNPC) and CRPC. Treatments effects in CNPC were also compared to androgen deprivation by surgical castration. Compared to saline treated controls, tumor growth was significantly inhibited by the AR-ASO (34%) and was comparable to that of surgical castration (38%). In the CRPC model, significant suppression of tumor growth (10% vs control) was also observed in mice treated with the AR-ASO. Furthermore, strong inhibition of AR expression and activity was observed in AR-ASO-treated mice harboring either CNPC or CRPC, but not in mice treated with surgical castration. Gene expression profiling using the Fluidigm Biomark platform revealed that 40 AR-dependent target genes were significantly altered in CNPC after treatment with the AR-ASO; 34 of these genes were also significantly changed following castration. A decrease of ERK phosphorylation in was observed in AR-ASO-treated mice in both CNPC and CRPC intervention models and was associated with decreased protein levels of AR. These findings demonstrate that treatment with generation 2.5 AR-ASO is effective against preclinical mouse models of prostate cancer and may provide a promising approach to overcoming treatment resistance of CRPC.

Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Barry R. Davies, Hayley Campbell, Yuji Hatanaka, Yutaka Yamamoto, Nobutaka Shimizu, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Inhibition of mouse PTEN-deficient prostate cancer with next generation antisense oligonucleotide targeting the androgen receptor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4212. doi:10.1158/1538-7445.AM2015-4212