BERKELEY, CA (UroToday.com) - In recent years tremendous progress has been made in therapies targeting the androgen receptor in castration resistant prostate cancer (CRPC). Basically there are two principles to prevent malignant androgen receptor signaling in prostate cancer. Either all sites of steroidogenesis including adrenal and intratumoral sources of androgens are targeted, or receptor antagonists with high affinity to the androgen receptor block androgen binding and its transcription factor activity. Although marked survival benefits with these new strategies became evident in clinical trials, concerns have arisen about pending therapy resistance, antiandrogen withdrawal phenomena or cross resistance mechanisms. Furthermore, androgen deprivation and receptor antagonism are associated with severe side effects on cardiometabolic and musculoskeletal health. Therefore, the rationale for intermittent androgen deprivation weighting cancer therapy and men´s health mutually remained under constant discussion. In addition, current evidence revealed that prostate cancer growth depends on rather low testosterone levels when androgen receptor expression is elevated and receptor function is facilitated by other androgen receptor aberrations.
In this study we realized an intriguing therapeutic effect from external testosterone boosts but below physiological ranges in CRPC models in vitro and in vivo. In these cell models, castration resistance predominantly is represented by androgen receptor over expression and the occurrence of androgen receptor splice variants but not by point mutations in the ligand-binding domain of the receptor, which permit a variety of activating ligands besides testosterone and dihydrotestosterone (DHT). Previous studies from other groups defined an elevated androgen receptor expression as liability for tumor cell survival. In our experiments CRPC cells with androgen receptor over expression treated with testosterone boosts respond with a massive decrease in tumor cell proliferation. Cells surviving the testosterone boost feature much lower androgen receptor and splice variant expression which represents a less malignant phenotype of prostate cancer. Moreover, such remaining cells are again susceptible to androgen deprivation. Therefore, we regard the testosterone boost as a reset in a process of accumulating androgen receptor expression to resist castration. Clinical trials, exercised with caution, are warranted for this variant of intermittent androgen deprivation boosted with a slight androgen supplementation when castration resistance or therapy resistance is represented by over expressed androgen receptor.
Written by:
Paul Thelen, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Department of Urology, Georg-August-University, 37099 Göttingen, Germany
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