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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Androgen receptor (AR) activity drives prostate cancer growth, and resistance to antiandrogen therapies is a major clinical challenge.
• Antisense oligonucleotides (ASOs) offer a novel strategy to inhibit gene expression, including AR.
• Castration-resistant prostate cancer (CRPC) requires new therapeutic approaches to overcome treatment resistance.

Purpose of the Study:

• To evaluate the efficacy of a novel antisense oligonucleotide (ASO) targeting the androgen receptor (AR) in preclinical models of prostate cancer.
• To investigate the potential of combining AR-ASO therapy with AKT inhibition to overcome resistance mechanisms.
• To assess the therapeutic benefit and survival impact of this combination strategy in advanced CRPC models.

Main Methods:

• Utilized a Generation-2.5 antisense oligonucleotide (ASO) designed to target the mouse androgen receptor (AR).
• Employed genetically engineered mouse models that mimic human prostate cancer progression.
• Administered a combination therapy of AR-ASO and the pan-AKT inhibitor AZD5363.

Main Results:

• The AR-ASO demonstrated efficacy in reducing AR activity in preclinical models.
• Combination therapy with AR-ASO and AZD5363 effectively circumvented reciprocal feedback between AR and PI3K/AKT signaling.
• The combined treatment significantly improved therapeutic responses and prolonged survival in a clinically relevant mouse model of advanced CRPC.

Conclusions:

• Antisense oligonucleotides (ASOs) targeting the androgen receptor (AR) represent a viable therapeutic strategy for castration-resistant prostate cancer (CRPC).
• Combining AR-ASO therapy with AKT inhibition overcomes resistance pathways and enhances treatment efficacy.
• These preclinical findings support the development of AR-ASO and AKT inhibitor combinations for advanced CRPC treatment.