Abiraterone Steroidal Metabolites as Biomarkers for Treatment Resistance in Prostate Cancer
Abstract
First-line treatment for advanced (metastatic) prostate cancer (PCa) is androgen deprivation therapy (ADT), either by surgical or medical castration. In many cases the cancer becomes resistant, and castration resistant prostate cancer (CRPC) develops. Abiraterone, given orally as the prodrug abiraterone acetate, is used to treat CRPC and now is used as an upfront treatment in patients with castration-sensitive prostate cancer (CSPC). Abiraterone treatment improves overall survival; however, drug resistance eventually occurs, and patients die. In our previous studies, we found that abiraterone is metabolized in patients to7 steroidal metabolites and the first step is dependent on the 3-hydroxysteroid dehydrogenase (3HSD) enzyme which is encoded by HSD3B1 gene. In vitro and in vivo studies showed that abiraterone metabolites had opposing activities toward prostate tumor cells. Overall this project aims to investigate the steroidogenic metabolism of abiraterone and identify biomarkers of resistance. Here, we studied the pharmacokinetics of abiraterone metabolites after a single dose of abiraterone acetate in healthy subjects and used the data to normalize the levels of the metabolites in CSPC patients treated with abiraterone acetate to evaluate the association between abiraterone metabolites and the status of the HSD3B1. My results suggest no association between HSD3B1genotype and the formation of abiraterone metabolites. In prostate cancer cell lines, I found that abiraterone metabolites will shift the metabolism of endogenous steroids and also mediate the expression of the androgen receptor-regulated genes. These data suggest that abiraterone metabolites may serve as indirect cause of treatment resistance in CSPC patients treated with abiraterone acetate
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2020
- Accession Number
- AD1119627
Entities
People
- Mohammad Alyamani