Targeting Castration-resistant Prostate Cancer with Androgen Receptor Antisense Oligonucleotide Therapy

Overview

Journal JCI Insight

Specialties Biomedical Engineering
General Medicine

Date 2019 Sep 6

PMID 31484823

Citations 21

Authors

Marco A De Velasco

Yurie Kura

Kazuko Sakai

Yuji Hatanaka

Barry R Davies

Hayley Campbell

Stephanie Klein

YoungSoo Kim

A Robert MacLeod

Koichi Sugimoto

Kazuhiro Yoshikawa

Kazuto Nishio

Hirotsugu Uemura

Affiliations

Soon will be listed here.

Abstract

Sustained therapeutic responses from traditional and next-generation antiandrogen therapies remain elusive in clinical practice due to inherent and/or acquired resistance resulting in persistent androgen receptor (AR) activity. Antisense oligonucleotides (ASO) have the ability to block target gene expression and associated protein products and provide an alternate treatment strategy for castration-resistant prostate cancer (CRPC). We demonstrate the efficacy and therapeutic potential of this approach with a Generation-2.5 ASO targeting the mouse AR in genetically engineered models of prostate cancer. Furthermore, reciprocal feedback between AR and PI3K/AKT signaling was circumvented using a combination approach of AR-ASO therapy with the potent pan-AKT inhibitor, AZD5363. This treatment strategy effectively improved treatment responses and prolonged survival in a clinically relevant mouse model of advanced CRPC. Thus, our data provide preclinical evidence to support a combination strategy of next-generation ASOs targeting AR in combination with AKT inhibition as a potentially beneficial treatment approach for CRPC.

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