Abstract 1582: Therapeutic potential of combination therapy using a next generation antisense oligonucleotide targeting the androgen receptor and AKT inhibition with AZD5363 in genetically engineered mouse models of prostate cancer
Authors: Velasco Marco A. De , Kura Yurie , Ando Naomi , Sugimoto Koichi , Sakai Kazuko , Davies Barry R. , Kim Youngsoo , MacLeod A. Robert , Nozawa Masahiro , Yoshimura Kazuhiro , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: July 2017

Abstract
Prostate cancer is highly dependent on androgen receptor (AR) and PI3K/AKT signaling pathways for survival and disease progression. Preclinical evidence suggests that combinatorial approaches targeting both AR and PI3K/AKT activity improves treatment efficacy. However, sustained responses from traditional and next-generation anti-androgen therapies targeting AR remain elusive in clinical practice due to inherent/acquired resistance resulting in lethal castration-resistant prostate cancer (CRPC). Mechanisms for continued AR transcriptional activity may be ligand dependent or independent but still require AR gene expression. Persistent AR gene expression is a key feature of CRPC. Thus, blocking AR gene expression by antisense oligonucleotides (ASO) is a logical approach to CRPC. We previously showed that monotherapy with ISIS581088, a generation 2.5 ASO targeting mouse AR, demonstrated strong antitumor activity in a transgenic mouse model of PTEN-deficient prostate cancer. In this study we show the antitumor effects of combined therapy of ISIS581088 and AZD5363, a potent AKT inhibitor and demonstrate the therapeutic benefit of combination therapy in a clinically relevant mouse model of CRPC. Sixteen-week-old mice with PTEN-/- castration-naïve prostate tumors were treated with ISIS581088 and AZD5363 alone or in combination for four weeks. Tumor growth inhibition rates were 41.2%, 20.2% and 54.4% for ISIS581088, AZD5363 and ISIS581088/AZD5363 treatment groups, respectively, P&lt;0.001. In a model of mouse CRPC, 16-week-old mice with PTEN-/- castration-resistant prostate tumors (eight weeks post castration) experienced reduced tumor burden with all treatments but no enhancement was observed when the compounds were administered in combination compared with monotherapy drug treatments. In a randomized trial of advanced CRPC in PTEN/P53 double knockout mice, combination therapy significantly increased overall survival. Median survival were 18, 17 21, 22, and 38 days for control vehicle, control ASO, ISIS581088, AZD5363 and ISIS581088/AZD5363 treatment groups, respectively, P=0.041. In conclusion, our data shows that combination therapy significantly reduced tumor burden in mice with castration-naïve tumors compared to those treated with monotherapy. Notably, combination therapy did not produce an additive effect in an early stage CRPC intervention model. Still, combination therapy demonstrated a clear advantage in prolonging overall survival in a long-term randomized mouse trial of PTEN/P53-deficient CRPC. Thus, our data provides preclinical evidence to support that next generation ASOs targeting AR in combination with AKT inhibition is a potentially effective treatment approach for CRPC.
Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Koichi Sugimoto, Kazuko Sakai, Barry R. Davies, Youngsoo Kim, A. Robert MacLeod, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio , Hirotsugu Uemura. Therapeutic potential of combination therapy using a next generation antisense oligonucleotide targeting the androgen receptor and AKT inhibition with AZD5363 in genetically engineered mouse models of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1582. doi:10.1158/1538-7445.AM2017-1582