Letter | Published:

Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy

Nature volume 533, pages 547551 (26 May 2016) | Download Citation

Subjects

Abstract

Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis1,2. Abiraterone is metabolized in patients to Δ4-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5α-reductase substrates, such as testosterone3. 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.

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Primary accessions

Gene Expression Omnibus

Data deposits

Microarray results have been deposited in the NCBI Gene Expression Omnibus database under accession number GSE75387.

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Acknowledgements

We thank T. Penning for use of the AKR1C2 construct and D. Russell for LY191704. This work was supported in part by funding from a Howard Hughes Medical Institute Physician-Scientist Early Career Award (to N.S.), a Prostate Cancer Foundation Challenge Award (to N.S.), an American Cancer Society Research Scholar Award (12-038-01-CCE; to N.S.), grants from the National Cancer Institute (R01CA168899, R01CA172382, and R01CA190289; to N.S.), a grant from the US Army Medical Research and Materiel Command (PC121382 to Z.L.), a Prostate Cancer Foundation Young Investigator Award (to Z.L.), grants from the National Cancer Institute (P01 CA163227 and P50 CA090381), and a Prostate Cancer Foundation Challenge Award (to S.P.B.). Janssen provided clinical trial support (to M.-E.T.).

Author information

Affiliations

  1. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA

    • Zhenfei Li
    • , Mohammad Alyamani
    • , Jianneng Li
    •  & Nima Sharifi
  2. Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA

    • Kevin Rogacki
    •  & Mohamed Abazeed
  3. Departments of Pharmacology and Internal Medicine, Division of Endocrinology and Metabolism, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA

    • Sunil K. Upadhyay
    •  & Richard J. Auchus
  4. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA

    • Steven P. Balk
  5. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Mary-Ellen Taplin
  6. Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA

    • Nima Sharifi
  7. Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA

    • Nima Sharifi

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Contributions

Z.L. performed gene expression, metabolism and mouse work. M. Alyamani performed mass spectrometry metabolism work. J.L. performed immunoblots. S.K.U. performed chemical syntheses. K.R. and M. Abazeed performed the microarray GSEA analysis. M.-E.T. and S.P.B. designed and performed the clinical trial. Z.L., M. Alaymani, R.J.A. and N.S. designed the studies and wrote the manuscript. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Nima Sharifi.

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    Supplementary Information

    This file contains Supplementary Methods and Supplementary Table 1.

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DOI

https://doi.org/10.1038/nature17954

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