Is androgen receptor activity in metastatic prostate cancer a good biomarker for bipolar androgen therapy?
Nahuel Peinetti, … , Marijo Bilusic, Kerry L. Burnstein
Nahuel Peinetti, … , Marijo Bilusic, Kerry L. Burnstein
Published December 1, 2022
Citation Information: J Clin Invest. 2022;132(23):e165357. https://doi.org/10.1172/JCI165357.
View: Text | PDF
Commentary

Is androgen receptor activity in metastatic prostate cancer a good biomarker for bipolar androgen therapy?

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.

Authors

Nahuel Peinetti, Marijo Bilusic, Kerry L. Burnstein

×

Figure 1

ARAMW is a potential biomarker of BAT response in metastatic CRPC.

Options: View larger image (or click on image) Download as PowerPoint
ARAMW is a potential biomarker of BAT response in metastatic CRPC. Patie...
Patients with advanced PC are commonly treated with ADT but generally progress to incurable CRPC. The COMBAT-CRPC clinical trial enrolled patients with metastatic CRPC (mCRPC) and treated them with BAT for 12 weeks with three cycles of SPA with ongoing ADT. Sena et al. performed RNA-Seq and IHC analysis of metastatic tumor biopsies obtained from patients before treatment and after the three cycles of BAT. The authors used RNA-Seq data to demonstrate that high ARAMW in pretreatment metastatic biopsies was associated with BAT response, including lower circulating PSA, decreased tumor volume, and higher overall survival (OS). IHC data showed that c-MYC was decreased in patients who responded to BAT. Experiments using PC cell lines showed that SPA, acting through the AR, decreased c-MYC and reduced cell growth, although other AR-regulated factors in addition to c-MYC may also be involved.