Abiraterone Steroidal Metabolites as Biomarkers for Treatment Resistance in Prostate Cancer
Technical Report,01 Aug 2018,31 Jul 2019
Cleveland Clinic Foundation Cleveland United States
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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. 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 to 7 steroidal metabolites. 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 will use the data to normalize the levels of the metabolites in patients. I also found that in prostate cancer cell lines, abiraterone metabolites will shift the metabolism of endogenous steroids and also mediate the expression of the androgen receptor-regulated genes. In the following funding year I will confirm the results in other prostate cancer cell line and will evaluate the 7 metabolites in patients and determine the relationship between metabolite levels and patient clinical outcomes to identify a biomarker of treatment resistance.
- Medicine and Medical Research