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
• Journal: JCI insight (JCI Insight) Vol. 4 Issue 17 (09 05 2019) ISSN: 2379-3708 [Electronic] United States
• PMID: 31484823 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AR protein, human
• AR protein, mouse
• Antineoplastic Agents
• Oligonucleotides, Antisense
• Pyrimidines
• Pyrroles
• Receptors, Androgen
• Proto-Oncogene Proteins c-akt
• capivasertib

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Disease Models, Animal
• Drug Resistance, Neoplasm (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Oligonucleotides, Antisense (pharmacology, therapeutic use)
• Phosphatidylinositol 3-Kinases (metabolism)
• Prostatic Neoplasms (drug therapy, genetics, pathology)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, genetics, pathology)
• Proto-Oncogene Proteins c-akt (pharmacology)
• Pyrimidines
• Pyrroles
• Receptors, Androgen (metabolism)
• Signal Transduction (drug effects)
• Transcriptome