title: The DHEA-sulfate depot following P450c17 inhibition supports the case for AKR1C3 inhibition in high risk localized and advanced castration resistant prostate cancer.
abstract: Prostate cancer is the second leading cause of cancer death in the United States. Treatment of localized high-risk disease and de novo metastatic disease frequently leads to relapse. These metastatic castration resistant prostate cancers (mCRPC) claim a high mortality rate, despite the extended survival afforded by the growing armamentarium of androgen deprivation, radiation and immunotherapies. Here, we review two studies of neoadjuvant treatment of high-risk localized prostate cancer prior to prostatectomy, the total androgen pathway suppression (TAPS) trial and the neoadjuvant abiraterone acetate (AA) trial. These two trials assessed the efficacy of the non-specific P450c17 inhibitor, ketoconazole and the specific P450c17 inhibitor, AA, to inhibit tissue and serum androgen levels. Furthermore, a novel and validated stable isotope dilution liquid chromatography electrospray ionization selected reaction monitoring mass spectrometry assay was used to accurately quantify adrenal and gonadal androgens in circulation during the course of these trials. The adrenal androgens, Δ(4)-androstene-3,17-dione, dehydroepiandrosterone and dehydroepiandrosterone sulfate were significantly reduced in the patients receiving ketoconazole or AA compared to those who did not. However, in both trials, a significant amount of DHEA-S (∼20 μg/dL) persists and thus may serve as a depot for intratumoral conversion to the potent androgen receptor ligands, testosterone (T) and 5α-dihydrotestosterone (DHT). The final step in conversion of Δ(4)-androstene-3,17-dione and 5α-androstanedione to T and DHT, respectively, is catalyzed by AKR1C3. We therefore present the case that in the context of the DHEA-S depot, P450c17 and AKR1C3 inhibition may be an effective combinatorial treatment strategy.
authors.affiliation: Centers for Cancer Pharmacology and Excellence of Environmental Toxicology (CEET), Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Tamae
authors.affiliation: Fred Hutchinson Cancer Center, University of Washington, Seattle, WA 98109, USA.
authors.forename: Elahe
authors.initials: E
authors.lastname: Mostaghel
authors.affiliation: Fred Hutchinson Cancer Center, University of Washington, Seattle, WA 98109, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Montgomery
authors.affiliation: Fred Hutchinson Cancer Center, University of Washington, Seattle, WA 98109, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Balk
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.affiliation: Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Taplin
authors.affiliation: Centers for Cancer Pharmacology and Excellence of Environmental Toxicology (CEET), Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA. Electronic address: penning@upenn.edu.
authors.forename: Trevor M
authors.initials: TM
authors.lastname: Penning
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000074425:Aldo-Keto Reductase Family 1 Member C3; D019314:Dehydroepiandrosterone Sulfate / Q000378:metabolism*; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism*; D012306:Risk; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D019314:Dehydroepiandrosterone Sulfate; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase
keywords: AKR1C3; Abiraterone acetate; Castration resistant prostate cancer; DHEA-sulfate; Mass spectrometry