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Is androgen receptor activity in metastatic prostate cancer a good biomarker for bipolar androgen therapy?
Nahuel Peinetti1,2, Marijo Bilusic2,3, Kerry L Burnstein1,2,4
1Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida, USA.
Abstract:
Androgen deprivation therapy (ADT) is the longstanding treatment for advanced prostate cancer (PC) because androgen receptor (AR) is the key therapeutic vulnerability for this disease. Bipolar androgen therapy (BAT) - the rapid cycling of supraphysiologic androgen (SPA) and low serum testosterone levels - is an alternative concept, but not all patients respond and acquired resistance can occur. In this issue of the JCI, Sena et al. developed a gene signature indicative of high AR activity to predict patient response to BAT, including a decline in both serum prostate-specific antigen (PSA) and tumor volume. Preclinical models showed that AR-mediated suppression of MYC, known to drive PC, was associated with decreased cell growth following SPA treatment. Because BAT eventually leads to resistance, the authors tested cycling between SPA and AR antagonism in a patient-derived xenograft and observed a delay in tumor growth. These findings represent a major step toward the informed use of BAT for advanced PC.
Insights
Researchers developed a gene signature to predict response to bipolar androgen therapy (BAT) for advanced prostate cancer (PC). This approach identifies patients likely to benefit from BAT, potentially overcoming treatment resistance.
Area of Science:
- Oncology
- Molecular Biology
Background:
- Androgen deprivation therapy (ADT) is standard for advanced prostate cancer (PC), targeting the androgen receptor (AR).
- Bipolar androgen therapy (BAT), cycling high and low testosterone, is an alternative but faces response variability and resistance.
- Identifying predictive biomarkers for BAT is crucial for effective PC treatment.
Purpose of the Study:
- To develop a gene signature predicting patient response to bipolar androgen therapy (BAT) in advanced prostate cancer (PC).
- To investigate the role of AR activity and MYC in BAT response and resistance.
- To explore strategies for overcoming BAT resistance using combined therapies.
Main Methods:
- Development of a gene signature based on AR activity levels.
- Analysis of patient response to BAT, including serum prostate-specific antigen (PSA) and tumor volume changes.
- Preclinical studies in patient-derived xenografts to assess BAT efficacy and resistance mechanisms.
- Testing of cyclical SPA and AR antagonism to delay tumor growth.
Main Results:
- A gene signature indicative of high AR activity successfully predicted patient response to BAT.
- SPA treatment suppressed MYC, leading to decreased cell growth in preclinical PC models.
- Cycling between SPA and AR antagonism delayed tumor growth in patient-derived xenografts, suggesting a strategy to overcome resistance.
Conclusions:
- A novel gene signature can identify patients likely to respond to BAT for advanced PC.
- Understanding AR-MYC interactions provides insights into BAT mechanisms and resistance.
- Combined cyclical SPA and AR antagonism shows promise for managing advanced PC and overcoming BAT resistance.
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