Understanding the Relative Contributions of and Critical Enzymes for the Three Pathways for Intracrine Metabolism of Testicular Androgens in Advanced Prostate Cancer
Abstract
Castration depletes circulating testosterone (T) and prostate cancer (CaP) regresses, however androgen deprivation therapy (ADT) is palliative and CaP recurs as castration-recurrent/resistant 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2017
- Accession Number
- AD1058762
Entities
People
- David S Watt
Organizations
- University of Kentucky