Moving Towards Precision Urologic Oncology: Targeting Enzalutamide-resistant Prostate Cancer and Mutated Forms of the Androgen Receptor Using the Novel Inhibitor Darolutamide (ODM-201)

被引：81

作者：

Borgmann, Hendrik ^{[1
,2
]}

Lallous, Nada ^{[1
]}

Ozistanbullu, Deniz ^{[1
,3
]}

Beraldi, Eliana ^{[1
]}

Paul, Naman ^{[1
]}

Dalal, Kush ^{[1
]}

Fazli, Ladan ^{[1
]}

Haferkamp, Axel ^{[2
]}

Lejeune, Pascale ^{[4
]}

Cherkasov, Artem ^{[1
]}

Gleave, Martin E. ^{[1
]}

机构：

[1] Univ British Columbia, Vancouver Prostate Ctr, Dept Urol Sci, Vancouver, BC V5Z 1M9, Canada

[2] Univ Med Johannes Gutenberg Univ Mainz, Dept Urol, Mainz, Germany

[3] Univ Hosp Frankfurt, Dept Urol, Frankfurt, Germany

[4] Bayer AG, Berlin, Germany

来源：

EUROPEAN UROLOGY | 2018年 / 73卷 / 01期

关键词：

Castration-resistant prostate cancer; Personalized medicine; Precision oncology; Treatment sequence; AR mutation; ctDNA; MECHANISMS;

D O I：

10.1016/j.eururo.2017.08.012

中图分类号：

R5 [内科学]; R69 [泌尿科学（泌尿生殖系疾病）];

学科分类号：

1002 ; 100201 ;

摘要：

Darolutamide (ODM-201) is a novel androgen receptor (AR) antagonist with a chemical structure distinctly different from currently approved AR antagonists that targets both wild-type and mutated ligand binding domain variants to inhibit AR nuclear translocation. Here, we evaluate the activity of darolutamide in enzalutamide-resistant castration resistant prostate cancer (CRPC) as well as in AR mutants detected in patients after treatment with enzalutamide, abiraterone, or bicalutamide. Darolutamide significantly inhibited cell growth and AR transcriptional activity in enzalutamide-resistant MR49F cells in vitro, and led to decreased tumor volume and serum prostate-specific antigen levels in vivo, prolonging survival in mice bearing enzalutamide-resistant MR49F xenografts. Moreover, darolutamide inhibited the transcriptional activity of AR mutants identified in the plasma of CRPC patients progressing on traditional therapies. In particular, darolutamide significantly inhibited the transcriptional activity of the F877L, H875Y/T878A, F877L/T878A, and the previously unreported T878G AR mutants, that transform enzalutamide into a partial agonist. In silico cheminformatics computer modeling provided atomic level insights confirming darolutamide antagonist effect in F877L and T878G AR mutants. In conclusion, our results provide a rationale for further clinical evaluation of darolutamide in enzalutamide-resistant CRPC, in particular in combination with circulating tumor DNA assays that detect AR mutants sensitive to darolutamide, in a precision oncology setting. Patient summary: In this study we evaluated the novel drug darolutamide in preclinical models of prostate cancer. We found that darolutamide delays growth of enzalutamide-resistant prostate cancer, in particular in cells with mutated forms of the androgen receptor after previous treatment. Our data supports further evaluation of darolutamide in clinical trials. (c) 2017 Published by Elsevier B.V. on behalf of European Association of Urology.

引用

页码：4 / 8

页数：5

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