Doctoral dissertation (article) (G5)

Androgen receptor therapy resistance in prostate cancer: From the disease model to the mechanisms




List of AuthorsHuhtaniemi Riikka

PublisherUniversity of Turku

PlaceTurku

Publication year2024

ISBN978-951-29-9632-2

eISBN978-951-29-9633-9

URLhttps://urn.fi/URN:ISBN:978-951-29-9633-9


Abstract

Androgens act through the androgen receptor (AR) and are critical regulators of prostate differentiation and function, as well as prostate cancer (PCa) growth and survival. The development of treatment resistance in castration-resistant prostate cancer (CRPC) is a major clinical concern in PCa. Although several mechanisms contribute to the treatment resistance, the AR remains a key factor in progression of the disease.

In this study, VCaP xenograft bearing mice were surgically operated by performing orchiectomy (ORX) and/or adrenalectomy (ADX) and treated with antiandrogen to model the different hormonal therapies used. Until now, it has been assumed that, unlike human, the murine adrenal cortex does not produce androgens. Our data, however, clearly indicates a contribution of the mouse adrenal gland to the intratumoral steroids in the castration-resistant VCaP tumors and to their androgen dependent growth. This is significant as it demonstrates a similarity between rodents and humans and indicates that the data obtained from the mouse models likely translate to humans better than previously anticipated.

Using VCaP tumor xenografts, we have demonstrated that the antiandrogen (enzalutamide) first stabilized tumor size, decreased serum PSA levels, and reduced intratumoral androgens, but after the treatment resistance, tumors continued to grow and intratumoral testosterone and DHT elevated back to the level observed in non-treated castration-resistant tumors. Interestingly, the tumor growth rate after ADX was slower in comparison with tumors with enzalutamide treatment and no up-regulation of DHT was observed. In summary, the data suggest that antiandrogen therapy resistance in the VCaP xenografts is associated with high intratumoral DHT production and active androgen action. Consequently, resistance to hormonal treatments is mediated by continuous activation of the AR signaling pathway caused by e.g., increased expression of the AR, AR splice variants and reactivation of tumor androgen synthesis, which together ultimately leads to DHT-mediated receptor activation.


Last updated on 2024-21-02 at 08:32