Modeling Androgen Deprivation Therapy-Induced Prostate Cancer Dormancy and Its Clinical Implications

Area of Science:

• Oncology
• Cancer Biology
• Translational Research

Background:

• Treatment-induced tumor dormancy is a critical phase in cancer progression, characterized by dormant cancer cells that are resistant to therapy and can lead to recurrence and metastasis.
• Prostate cancer often enters a dormant state following androgen-deprivation therapy (ADT), but this phenomenon is poorly understood due to challenges in obtaining clinical samples and a lack of suitable models.

Purpose of the Study:

• To develop clinically relevant models for investigating ADT-induced prostate cancer dormancy.
• To characterize the dormancy subtypes and identify predictive biomarkers for ADT response.

Main Methods:

• Established ADT-induced dormant prostate cancer models using patient-derived xenografts (PDX) in mice by castration.
• Monitored dormancy status and tumor relapse, followed by morphologic and transcriptome profiling of pre- and post-castration PDX tissues.

Main Results:

• Successfully created eleven ADT-induced dormant prostate cancer models that recapitulate clinical ADT treatment courses.
• Identified two distinct ADT-induced dormancy subtypes with differences in morphology, gene expression, and relapse rates.
• Discovered pre-treatment transcriptomic differences that predispose tumors to ADT-induced dormancy.

Conclusions:

• Developed a novel, dormancy subtype-based gene signature for predicting ADT response in hormone-naïve prostate cancer.
• The gene signature is associated with clinical outcomes in castration-resistant prostate cancer patients treated with ADT or androgen-receptor pathway inhibitors.
• The established PDX models and predictive signature offer robust risk stratification for prostate cancer patients undergoing ADT.