Steroidogenesis in castration-resistant prostate cancer

Area of Science:

• Oncology
• Endocrinology
• Molecular Biology

Background:

• Castration-resistant prostate cancer (CRPC) often involves aberrant androgen receptor (AR) signaling.
• Adrenal gland-derived androgen precursors contribute to intracrine AR activation.
• Novel androgen pathway inhibitors (ARPIs) aim to suppress androgen synthesis and AR activation.

Purpose of the Study:

• To review evidence on pathological androgen milieu in prostate cancer.
• To explore how altered steroidogenesis and transport contribute to endocrine therapy resistance.
• To highlight alternative and backdoor androgen synthesis pathways in prostate cancer.

Main Methods:

• Literature review of current evidence on androgen metabolism and transport in prostate cancer.
• Analysis of steroidogenesis pathways, including classical, alternative, backdoor, and 11β-hydroxyandrostenedione pathways.
• Examination of AR signaling and its resistance mechanisms in the context of endocrine therapy.

Main Results:

• Resistance to ARPIs is linked to a persistent androgen milieu.
• Alternative, backdoor, and 11β-hydroxyandrostenedione pathways generate potent androgens (e.g., dihydrotestosterone, 11-ketotestosterone).
• These pathways contribute to intratumoral steroidogenesis, promoting resistance to endocrine therapy.

Conclusions:

• Altered androgen metabolism and transport create a pathological milieu in prostate cancer.
• This milieu drives resistance to endocrine therapies, including novel ARPIs.
• Targeting these specific steroidogenesis pathways may offer new therapeutic strategies for advanced prostate cancer.