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 2

Generation-2.5 ASO targeting mouse Ar decreases expression of full-length AR and putative splice variants.

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Generation-2.5 ASO targeting mouse Ar decreases expression of full-lengt...
Expression of full-length AR (AR-FL) and aberrant AR in mouse prostate tumors was determined by automated capillary electrophoresis with an AR antibody targeting the n-terminal domain (AR-NTD, aa204-221) and the ligand binding domain (AR-LBD, aa660-899, see Supplemental Figure 3C) in prostates from 20-week-old normal WT (Pten+/+) mice or prostate tumors from untreated and ISIS581088-treated Pten-deficient (Pten–/–) mice. ISI581088 was administered for 4 weeks (40 mg/kg/d for first week loading, followed by 3 weeks of maintenance dosing, 40 mg/kg 3×/week). The results are shown as a virtual blot (A) and electropherogram (B). AR-FL, putative AR-Vs and high molecular weight bands are represented by blue, red, and black arrows, respectively. Shaded areas in the electropherogram denote peaks after baseline correction. (C) Western blot of AR expression using anti–AR-NTD and anti–AR-LBD antibodies in prostate tumors from untreated Pten-KO mice and 14 days after orchidectomy or 10 days of treatment with ISIS581088 (ISIS581088 was administered according to the dosing schedule in Supplemental Figure 1A). GAPDH was used a loading control. (D) Plots of Ar mRNA expression by qPCR. Horizontal bars represent mean ± SEM, and diamonds represent individual samples; n = 3 mice/group. Significance represent Student-Newman-Keuls post hoc test for individual comparisons, upon significant 1-way ANOVA (Ar Ex2, F2,8 = 65.306, P < 0.001; Ar Ex7, F2,8 = 46.706, P < 0.001).