title: Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy.
abstract: Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis. Abiraterone is metabolized in patients to Δ(4)-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5α-reductase substrates, such as testosterone. Here, we show that D4A is converted to at least three 5α-reduced and three 5β-reduced metabolites in human serum. The initial 5α-reduced metabolite, 3-keto-5α-abiraterone, is present at higher concentrations than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while D4A concentrations rose, showing that dutasteride effectively blocks production of a tumour-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy.
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Zhenfei
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Alyamani
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Jianneng
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Rogacki
authors.affiliation: Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abazeed
authors.affiliation: Departments of Pharmacology and Internal Medicine, Division of Endocrinology and Metabolism, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Upadhyay
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Balk
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Taplin
authors.affiliation: Departments of Pharmacology and Internal Medicine, Division of Endocrinology and Metabolism, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Auchus
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.|Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.|Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Nima
authors.initials: N
authors.lastname: Sharifi
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism; D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000069501:Abiraterone Acetate / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use; D000284:Administration, Oral; D000726:Androgen Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000728:Androgens / Q000096:biosynthesis*; D000736:Androstenes / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D018450:Disease Progression; D000068538:Dutasteride / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C000608440:3-ketoabiraterone; D058891:5-alpha Reductase Inhibitors; C410798:AR protein, human; D000726:Androgen Antagonists; D000728:Androgens; D000736:Androstenes; D011944:Receptors, Androgen; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D000069501:Abiraterone Acetate; C089740:abiraterone; D000068538:Dutasteride