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Androgen–glucocorticoid interactions in the era of novel prostate cancer therapy

Key Points

  • Androgens are the main driver of prostate cancer growth, and androgen signalling often leads to castration-resistant prostate cancer (CRPC), which can continue to progress despite androgen-deprivation therapy (ADT)

  • Glucocorticoids have long been included in the treatment and management of patients with prostate cancer; however, glucocorticoid-related mechanisms can cause iatrogenic stimulation of prostate cancer growth and/or resistance to ADT

  • Abiraterone is an inhibitor of androgen synthesis that restrains androgen synthesis in the testes as well as prostate cancer cells, which has improved the outcomes of patients with prostate cancer

  • Enzalutamide, an androgen receptor (AR) blocker, prevents androgen binding to the AR, thus reducing translocation of the androgen–AR complex to the nucleus, inhibiting the expression of androgen target genes

  • Abiraterone inhibits glucocorticoid synthesis while blocking androgen synthesis, and is usually given with a synthetic glucocorticoid to prevent adrenal insufficiency; abiraterone-induced changes in steroidogenesis patterns can cause resistance to therapy

  • Increased glucocorticoid receptor (GR) expression has been observed in prostate cancer cells treated with enzalutamide; glucocorticoid–GR complexes can also activate certain AR target genes leading to enzalutamide resistance

Abstract

Great strides have been made in the treatment of castration-resistant prostate cancer (CRPC) with the development of new antiandrogens (enzalutamide) and more potent androgen synthesis inhibitors (abiraterone) that have both improved patient outcomes. These new drugs have also helped unravel the complex biology of androgen–androgen receptor driven prostate cancer and brought into prominence various mechanisms triggering the development of drug resistance and tumour cell survival despite use of androgen deprivation therapy (ADT). The complex role of glucocorticoids in the treatment, management and progression of patients with CRPC is integral to these advances. Historically, glucocorticoid treatment has resulted in both subjective and objective responses in patients with advanced-stage prostate cancer. With the use of these new therapeutic agents, however, unexpected glucocorticoid-related mechanisms that can cause iatrogenic stimulation of prostate cancer growth have emerged, which might contribute to drug resistance and disease progression despite optimal ADT. For example, the upregulation of glucocorticoid receptors (GRs) during enzalutamide therapy results in glucocorticoid–GR-mediated regulation of androgen target genes, leading to escape from enzalutamide blockade. Thus, understanding the biological role of glucocorticoids in patients with prostate cancer is of major importance in the era of new and evolving antiandrogen therapies.

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Figure 1: Androgen synthesis and signalling pathways: drugs used for androgen deprivation therapy and to block androgen action.
Figure 2: Adrenal steroidogenic pathways in androgen synthesis: inhibition and consequences of abiraterone inhibition of 17α-hydroxylase to block androgen and cortisol synthesis.
Figure 3: Androgen action in a castration resistant prostate cancer cell via AR–ARE binding and potential consequences of enzalutamide blockade.

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Acknowledgements

We would like to acknowledge the assistance of Srilatha Swami in the preparation of the initial versions of the figures.

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Narayanan, S., Srinivas, S. & Feldman, D. Androgen–glucocorticoid interactions in the era of novel prostate cancer therapy. Nat Rev Urol 13, 47–60 (2016). https://doi.org/10.1038/nrurol.2015.254

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