Targeting castration-resistant prostate cancer with androgen receptor antisense oligonucleotide therapy
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
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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Research Article Endocrinology Therapeutics

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

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 4

Ar-ASO blockade is more effective at suppressing mouse Pten-deficient prostate tumor growth compared with other pharmacological antiandrogen therapies.

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Ar-ASO blockade is more effective at suppressing mouse Pten-deficient p...
The activity of ISIS581088 was compared with surgical castration and pharmacological AR inhibition. Pten-KO mice (32 weeks of age) were randomized as control or were assigned to ISIS581088 (ISI, 40 mg/kg, 1 week loading, 3 weeks maintenance), orchidectomy (Orch), enzalutamide (Enz, 30 mg/kg/day), apalutamide (Apa, 30 mg/kg/day), abiraterone (Abi, 200 mg/kg/day), and chlormadinone acetate (CMA, 100 mg/kg/day) treatment groups. Mice received treatment for 4 weeks, and untreated littermates were collected at baseline (BL), n = 4 mice/group. (A) Plots of mean ± SEM of GUT and prostate weights normalized to baseline means. Horizontal bars represent mean ± SEM, and diamonds represent individual mice. Significance represent Student-Newman-Keuls post hoc test for individual comparisons, upon significant 1-way ANOVA (GUT, F7,32 = 36.25, P < 0.001; prostate, F7,32 = 4.162, P < 0.001); *P < 0.05; **P < 0.01; ***P < 0.001. (B) Waterfall plot of individual treatment response based on prostate tumor weight normalized to median baseline level. (C) Representative images of whole genitourinary tracts and H&E-stained sections of mouse dorsal prostate (DP) and ventral prostate (VP) tumors. Scale in GUT represents mm (scale bars: 100 μm). Scale in GUT represents mm (scale bars: 100 μm). (D) Clustering analysis of differentiated expresses genes from qPCR-based panel Ar, core AR responsive, AR stimulating, proliferation, and apoptosis genes. Heatmap shows unsupervised hierarchical clustering using complete linkage and Pearson correlation.