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The testosterone paradox of advanced prostate cancer: mechanistic insights and clinical implications

Abstract

The discovery of the benefits of castration for prostate cancer treatment in 1941 led to androgen deprivation therapy, which remains a mainstay of the treatment of men with advanced prostate cancer. However, as early as this original publication, the inevitable development of castration-resistant prostate cancer was recognized. Resistance first manifests as a sustained rise in the androgen-responsive gene, PSA, consistent with reactivation of the androgen receptor axis. Evaluation of clinical specimens demonstrates that castration-resistant prostate cancer cells remain addicted to androgen signalling and adapt to chronic low-testosterone states. Paradoxically, results of several studies have suggested that treatment with supraphysiological levels of testosterone can retard prostate cancer growth. Insights from these studies have been used to investigate administration of supraphysiological testosterone to patients with prostate cancer for clinical benefits, a strategy that is termed bipolar androgen therapy (BAT). BAT involves rapid cycling from supraphysiological back to near-castration testosterone levels over a 4-week cycle. Understanding how BAT works at the molecular and cellular levels might help to rationalize combining BAT with other agents to achieve increased efficacy and tumour responses.

Key points

  • Androgens can drive prostate cancer growth providing the rationale for using deprivation of androgens as a first line of treatment for prostate cancer. Unfortunately, prostate cancer cells adapt to low androgen levels and eventually progress to a castration-resistant state.

  • Results of several studies have indicated a paradoxical decrease in tumour growth in prostate cancer models upon treatment with supraphysiological levels of testosterone. Evidence indicates several complementary mechanisms, including cell death and cytostasis, which might be responsible for paradoxical growth inhibition by supraphysiological testosterone.

  • Adaptive reliance on androgen signalling by castration-resistant prostate cancer cells becomes a therapeutic liability that can be exploited clinically through the administration of supraphysiological testosterone, an approach termed ‘bipolar androgen therapy’ (BAT). The term bipolar is used to emphasize that, with this strategy, rapid cycling occurs between two extremes: from supraphysiological back to near-castration testosterone levels over a 4-week cycle.

  • Understanding how BAT works at the molecular and cellular levels might help to develop biomarkers for patient stratification and to rationally combine BAT with other agents to achieve increased efficacy.

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Fig. 1: AR structure and signalling.
Fig. 2: Androgens in prostate homeostasis and regeneration.
Fig. 3: Mechanisms of action of supraphysiological testosterone.

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Acknowledgements

S.K. is partly supported by the W81XWH1910724, 1R01CA243184 and PCF Challenge awards. R.K. is supported by the W81XWH2210118 and PCF Young Investigator Award 21YOUN22. L.A.S. is supported by W81XWH2010079 and Johns Hopkins University Clinician-Scientist Award.

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Kumar, R., Sena, L.A., Denmeade, S.R. et al. The testosterone paradox of advanced prostate cancer: mechanistic insights and clinical implications. Nat Rev Urol 20, 265–278 (2023). https://doi.org/10.1038/s41585-022-00686-y

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