Understanding the Relative Contributions of and Critical Enzymes for the Three Pathways for Intracrine Metabolism of Testicular Androgens in Advanced Prostate Cancer
Technical Report,30 Sep 2016,29 Sep 2017
University of Kentucky Lexington United States
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Castration depletes circulating testosterone T and prostate cancer CaP regresses, however androgen deprivation therapy ADT is palliative and CaP recurs as castration-recurrentresistant CaP CRPC and causes death. One mechanism for CaP resistance is intratumoral intracrine androgen metabolism, which is the conversion of weak adrenal androgens, dehydroepiandrosterone DHEA or androstenedione ASD to testicular androgens, T and dihydrotestosterone DHT. There are 3 androgen metabolism pathways for DHT synthesis, the frontdoor and primary and secondary backdoor pathways. The timeline of intratumoral T and DHT production, the relative contribution of the 3 pathways and enzyme and pathway redundancy that drive CaP persistence after initiation of ADT to allow recurrence remain poorly understood. The central hypothesis of this report, better understanding of intracrine androgen metabolism during ADT will identify new targets to reduce T and DHT production. These studies will lead to the identification of the dominant androgen metabolism pathway that drives CaP persistence during ADT will reveal new druggable targets. Fluorescent androgens will identify the critical enzymes that drive the terminal steps of the frontdoor and primary and secondary backdoor pathways of androgen metabolism. Inhibitors that target the lead enzymes will be developed. If successful in preclinical studies, these inhibitors could be tested in patients with advanced CaP for extent of response and extension of survival.
- Medicine and Medical Research
- Anatomy and Physiology