A new study describes the characterization of the mechanisms underlying responses to supraphysiological testosterone therapy (SPT) for men with castration-resistant prostate cancer (CRPC). The findings in patient-derived xenografts (PDXs) show that SPT results in sustained suppression of AR-V7 and E2F signalling and the DNA damage response (DDR) in responders, describing potential mechanisms of tumour growth inhibition by SPT.

SPT results in sustained suppression of AR-V7 and E2F signalling and the DNA damage response

Previous studies have shown that treatment of CRPC with SPT can be effective in some patients. “Despite preclinical results showing inhibition of prostate cell proliferation by SPT and positive results from clinical trials, use of SPT in advanced prostate cancer is still highly debated by clinicians,” explains senior author Eva Corey from the University of Washington. “However, patients failing enzalutamide have very limited treatment options, and SPT presents an option for durable response and improved quality of life for some of these men.” Thus, Corey’s team set out to study mechanisms of SPT action and to discover biomarkers to identify those patients who respond.

Using advanced prostate cancer PDXs in mice, the team identified four PDXs that responded to SPT with tumour growth inhibition. These PDXs endogenously had lower proliferation scores and E2F signalling scores but higher androgen receptor (AR) mRNA levels, higher AR activity score and higher AR-V7 junction reads than PDXs that did not respond.

The team then explored SPT response in three CRPC PDXs that were resistant to enzalutamide. These models had varied responses to SPT: one PDX showed durable, the second transient and the third no growth suppression. In all three models during SPT, AR and ARV7 expression was downregulated but AR target gene expression was upregulated. By contrast, AR-V7 target gene expression was downregulated in SPT-responding PDXs only and was restored when the transiently responding PDXs became SPT resistant. Furthermore, the MYC–E2F pathway and DNA replication and DDR programmes were repressed in the responding PDX models and were also restored in the transient responder upon SPT resistance, indicating the mechanism of growth inhibition caused by SPT.

“This first molecular insight into SPT response and resistance together with a clinical case report provide evidence to nominate patients with DDR deficiency as remarkable and durable SPT responders,” comments Corey. “Furthermore, our data showed that enzalutamide rechallenge upon SPT resistance resulted in PSA level decreases but did not inhibit tumour progression, highlighting the need for monitoring radiographic progression and not relying on PSA levels to make conclusions about SPT efficacy.”

The team is now working to identify co-drivers of the observed DDR pathway inhibition for therapeutic targeting to augment SPT effectiveness. They are also investigating AR signalling differences between SPT responders and non-responders to identify biomarkers for patient selection.