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Targeting castration-resistant prostate cancer with androgen receptor antisense oligonucleotide therapy
Marco A. De Velasco, … , Kazuto Nishio, Hirotsugu Uemura
Marco A. De Velasco, … , Kazuto Nishio, Hirotsugu Uemura
Published September 5, 2019
Citation Information: JCI Insight. 2019;4(17):e122688. https://doi.org/10.1172/jci.insight.122688.
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Research Article Endocrinology Therapeutics

Targeting castration-resistant prostate cancer with androgen receptor antisense oligonucleotide therapy

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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.

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

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Figure 6

Expression profiling of AR-responsive genes in mouse Pten-deficient prostate tumors treated with ISIS581088.

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Expression profiling of AR-responsive genes in mouse Pten-deficient pros...
Sixteen-week-old mice with castration-naive (CNPC) or castration-resistant prostate tumors (CRPC, 6 weeks after surgical castration) were treated with saline (n = 5), control ASO (n = 6), or ISIS581088 (n = 6) for 4 weeks as described in Figure 3A and Figure 5A. Prostate tumors were collected for multiplex gene expression analysis of AR responsive genes using the Fluidigm analysis platform. (A) Heatmap and unsupervised hierarchical clustering (average linkage, Euclidean distance metric) of 86 AR-responsive genes after Ar silencing with ISIS581088 (see Supplemental Table 2). (B) Top biological processes enriched after Ar silencing in castration-naive prostate tumors.

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