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

Autor: A. Robert MacLeod, Kazuhiro Yoshikawa, Kazuko Sakai, Youngsoo Kim, Hayley Campbell, Koichi Sugimoto, Stephanie Klein, Marco A. De Velasco, Yurie Kura, Barry R. Davies, Yuji Hatanaka, Hirotsugu Uemura, Kazuto Nishio
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
medicine.drug_class
Antineoplastic Agents
Castration resistant
urologic and male genital diseases
Antiandrogen
Mice
Phosphatidylinositol 3-Kinases
03 medical and health sciences
Prostate cancer
0302 clinical medicine
Pharmacotherapy
Antisense Oligonucleotide Therapy
Animals
Humans
Medicine
Pyrroles
Protein kinase B
PI3K/AKT/mTOR pathway
Mice
Knockout
business.industry
Prostatic Neoplasms
General Medicine
Oligonucleotides
Antisense
medicine.disease
Gene Expression Regulation
Neoplastic
Mice
Inbred C57BL
Androgen receptor
Disease Models
Animal
Prostatic Neoplasms
Castration-Resistant
Pyrimidines
030104 developmental biology
Drug Resistance
Neoplasm
Receptors
Androgen
030220 oncology & carcinogenesis
Cancer research
Transcriptome
business
Proto-Oncogene Proteins c-akt
Research Article
Signal Transduction
Zdroj: JCI Insight. 4
ISSN: 2379-3708
DOI: 10.1172/jci.insight.122688
Popis: 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.
Databáze: OpenAIRE
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