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 3

Antitumor activity of ISIS581088 in mouse Pten-deficient prostate tumors.

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Antitumor activity of ISIS581088 in mouse Pten-deficient prostate tumors...
(A) Experimental design for drug intervention model. Mice were randomized into vehicle-treated (n = 8), control ASO (n = 6), or ISIS581088 (n = 12) cohorts, and mice 4 weeks after surgical castration (Orch, n = 8) are also shown. Control ASO and ISIS581088 were administered i.p. for 4 weeks (40 mg/kg/d for first week loading, followed by 3 weeks of maintenance dosing, 40 mg/kg 3×/week). Data represent the pooled analysis from 2 independent experiments using age-matched mice. (B) Representative images of genitourinary tracts (GUT). Prostate tumors are highlighted by a yellow mask; scale represents mm. (C) Plots of GUT weight; horizontal bars represent mean ± SEM, and diamonds represent individual samples. Significance represent Dunn’s post hoc test for individual comparisons, upon significant 1-way ANOVA on ranks (H3 = 25.632, P < 0.001). (D) Plots of prostate tumor area; horizontal bars represent mean ± SEM, and diamonds represent individual samples. Significance represent Student-Newman-Keuls post hoc test for individual comparisons, upon significant 1-way ANOVA (F3,30 = 82.965, P < 0.001). (E) Representative H&E-stained sections of mouse prostate tumors. Scale bars: 200 μm. (F) Plot of Ar mRNA expression determined by qPCR. Horizontal bars represent mean ± SEM, and diamonds represent individual samples. (G) Representative IHC photomicrographs of AR, the proliferation marker Ki67, and apoptosis marker cleaved caspase-3 in mouse prostate tumors. Plots represent percentage of positive-stained cells in epithelial cancer cells (n = 6 mice/group); horizontal bars represent mean ± SEM, and diamonds represent individual samples. Significance represent Student-Newman-Keuls post hoc test for individual comparisons, upon significant 1-way ANOVA (Ki67, F3,19 = 28.843, P < 0.001; c. casp-3, F3,19 = 16.276, P < 0.001). Scale bars: 100 μm. (H) Confirmation of AR inhibition and apoptosis induction by Western blot expression of AR, cleaved caspase-3. GAPDH was used a loading control.