AI Article Synopsis
- Traditional and next-generation antiandrogen therapies struggle in clinical settings due to resistance, leading to ongoing activity of the androgen receptor (AR).
- Antisense oligonucleotides (ASOs) offer a promising alternative treatment for castration-resistant prostate cancer (CRPC) by blocking gene expression related to AR.
- A combination treatment of a Generation-2.5 ASO targeting AR and an AKT inhibitor (AZD5363) showed improved efficacy and extended survival in advanced CRPC models, suggesting a viable therapeutic strategy.
Article 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777919 | PMC |
| http://dx.doi.org/10.1172/jci.insight.122688 | DOI Listing |
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