HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer
Mohammad Alyamani, Hamid Emamekhoo, Sunho Park, Jennifer Taylor, Nima Almassi, Sunil Upadhyay, Allison Tyler, Michael P. Berk, Bo Hu, Tae Hyun Hwang, William Douglas Figg, Cody J. Peer, Caly Chien, Vadim S. Koshkin, Prateek Mendiratta, Petros Grivas, Brian Rini, Jorge Garcia, Richard J. Auchus, Nima Sharifi
Mohammad Alyamani, Hamid Emamekhoo, Sunho Park, Jennifer Taylor, Nima Almassi, Sunil Upadhyay, Allison Tyler, Michael P. Berk, Bo Hu, Tae Hyun Hwang, William Douglas Figg, Cody J. Peer, Caly Chien, Vadim S. Koshkin, Prateek Mendiratta, Petros Grivas, Brian Rini, Jorge Garcia, Richard J. Auchus, Nima Sharifi
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Clinical Research and Public Health Endocrinology Oncology

HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer

Abstract

BACKGROUND. A common germline variant in HSD3B1(1245A>C) encodes for a hyperactive 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) missense that increases metabolic flux from extragonadal precursor steroids to DHT synthesis in prostate cancer. Enabling of extragonadal DHT synthesis by HSD3B1(1245C) predicts for more rapid clinical resistance to castration and sensitivity to extragonadal androgen synthesis inhibition. HSD3B1(1245C) thus appears to define a subgroup of patients who benefit from blocking extragonadal androgens. However, abiraterone, which is administered to block extragonadal androgens, is a steroidal drug that is metabolized by 3βHSD1 to multiple steroidal metabolites, including 3-keto-5α-abiraterone, which stimulates the androgen receptor. Our objective was to determine if HSD3B1(1245C) inheritance is associated with increased 3-keto-5α-abiraterone synthesis in patients. METHODS. First, we characterized the pharmacokinetics of 7 steroidal abiraterone metabolites in 15 healthy volunteers. Second, we determined the association between serum 3-keto-5α-abiraterone levels and HSD3B1 genotype in 30 patients treated with abiraterone acetate (AA) after correcting for the determined pharmacokinetics. RESULTS. Patients who inherit 0, 1, and 2 copies of HSD3B1(1245C) have a stepwise increase in normalized 3-keto-5α-abiraterone (0.04 ng/ml, 2.60 ng/ml, and 2.70 ng/ml, respectively; P = 0.002). CONCLUSION. Increased generation of 3-keto-5α-abiraterone in patients with HSD3B1(1245C) might partially negate abiraterone benefits in these patients who are otherwise more likely to benefit from CYP17A1 inhibition. FUNDING. Prostate Cancer Foundation Challenge Award, National Cancer Institute.

Authors

Mohammad Alyamani, Hamid Emamekhoo, Sunho Park, Jennifer Taylor, Nima Almassi, Sunil Upadhyay, Allison Tyler, Michael P. Berk, Bo Hu, Tae Hyun Hwang, William Douglas Figg, Cody J. Peer, Caly Chien, Vadim S. Koshkin, Prateek Mendiratta, Petros Grivas, Brian Rini, Jorge Garcia, Richard J. Auchus, Nima Sharifi

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Figure 3

HSD3B1(1245C) variant inheritance is associated with elevated generation of 3-keto-5α-Abi, 3α-OH-5α-Abi, and 3β-5α-Abi in 30 patients with CRPC treated with abiraterone.

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HSD3B1(1245C) variant inheritance is associated with elevated generatio...
(A) Higher levels of all three 5α-Abi metabolites were significantly present in patients with the HSD3B1(1245C) genotype. (B) Abiraterone, D4A, 3-keto-5β-Abi, 3α-OH-5β-Abi, and 3β-5β-Abi concentrations were not significantly correlated with HSD3B1 genotype. The levels of each metabolite were normalized to the 8-hour value in the PK study and the metabolite concentration for each patient at the fixed time point was predicted by a regression method. The significance of the difference among genotypes for each metabolite was determine by polyserial correlation analysis: 3-keto-5α-Abi, P = 0.002; 3α-OH-5α-Abi, P = 0.0001; 3β-5α-Abi, P = 0.006.