Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Clinical-Bioanalyticial Chemistry

Department

Chemistry

Subject Headings

Analytical Chemistry, Biomedical Research

Abstract

Despite an array of improved treatment options over the past decade, prostate cancer remains the second leading cause of cancer mortality for men in the United States. Abiraterone and galeterone are oral steroidal compounds that are used to treat metastatic castration-resistant prostate cancer (CRPC). Abiraterone blocks 17a-hydroxylase/17,20-lyase (CYP17A1), an enzyme required for androgen synthesis. Galeteron inhibits CYP17A1, blocks the androgen receptor (AR), and decreases AR protein levels. Both drugs share the same structure with endogenous androgens such as dehydroepiandrosterone, which are substrates for the enzyme, 3ß-hydroxysteroid dehydrogenase (3ßHSD). Metabolites of 3ßHSD undergo further metabolism to produce the AR ligand, testosterone and dihydrotestosterone.

Overall this project aimed to investigate the steroidogenic metabolism of abiraterone and galeterone and evaluate the metabolites’ role in prostate cancer. The background on prostate cancer, steroid biosynthesis, and treatment options is described in Chapter I. Chapter II describes the development and validation of a liquid chromatography mass spectrometry method LC-MS/MS to determine abiraterone metabolites. My method distinguished between all the diastereoisomers with conventional chromatographic conditions. In chapter III and IV my validated LC-MS/MS method was utilized to study the metabolism of abiraterone in vitro using prostate cancer cell lines and in vivo using mice. It also helped in determining abiraterone metabolites in a pharmacokinetic trial in healthy human subjects and in prostate cancer patients enrolled in several clinical trials. The trials aimed to evaluate the standard dose of abiraterone acetate, combining abiraterone acetate with androgen deprivation therapy (ADT), adding dutasteride (an SRD5A inhibitor), or increasing the frequency of the standard dose of abiraterone acetate. In chapter V, galeterone metabolism was studied in vitro and in vivo and the metabolites’ activities were evaluated for their roles in prostate cancer. Chapter VI discusses the overall conclusions and future directions.

This project identified a new subset of abiraterone and galeterone metabolites that are generated by steroidogenic enzyme conversion. These metabolites had opposing effects on prostate cancer. These findings suggest a common pathway for steroidal drugs with a Δ5, 3ß-hydroxyl structure. This project also provides new strategies in prostate cancer treatment that will make the current treatment options more beneficial.

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