Moving Towards Precision Urologic Oncology: Targeting Enzalutamide-resistant Prostate Cancer and Mutated Forms of the Androgen Receptor Using the Novel Inhibitor Darolutamide (ODM-201)
Moving Towards Precision Urologic Oncology: Targeting Enzalutamide-resistant Prostate Cancer and Mutated Forms of the Androgen Receptor Using the Novel Inhibitor Darolutamide (ODM-201)
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DOI：
10.1016/j.eururo.2017.08.012
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发表时间：
2018-01-01
期刊：
影响因子：
23.4
通讯作者：
Gleave, Martin E.
中科院分区：
文献类型：
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作者：
Borgmann, Hendrik;Lallous, Nada;Gleave, Martin E.
Darolutamide (ODM-201) 是一种新型雄激素受体 (AR) 拮抗剂，其化学结构与目前批准的 AR 拮抗剂明显不同，该拮抗剂同时靶向野生型和突变的配体结合域变体以抑制 AR 核转位。在这里，我们评估了 darolutamide 在恩杂鲁胺耐药的去势抵抗性前列腺癌 (CRPC) 中的活性，以及在恩杂鲁胺、阿比特龙或比卡鲁胺治疗后检测到的 AR 突变体中的活性。 Darolutamide 在体外显着抑制恩杂鲁胺耐药 MR49F 细胞的细胞生长和 AR 转录活性，并导致体内肿瘤体积和血清前列腺特异性抗原水平降低，延长了携带恩杂鲁胺耐药 MR49F 异种移植物的小鼠的生存期。此外，darolutamide 抑制了在接受传统疗法治疗的 CRPC 患者血浆中发现的 AR 突变体的转录活性。特别是，darolutamide 显着抑制 F877L、H875Y/T878A、F877L/T878A 和之前未报道的 T878G AR 突变体的转录活性，这些突变体将 enzalutamide 转化为部分激动剂。计算机化学信息学计算机模型提供了原子水平的见解，证实了 Darolutamide 在 F877L 和 T878G AR 突变体中的拮抗作用。总之，我们的结果为在恩杂鲁胺耐药的 CRPC 中进一步临床评估 darolutamide 提供了理论依据，特别是在精准肿瘤学环境中与检测对 darolutamide 敏感的 AR 突变体的循环肿瘤 DNA 测定相结合。 患者总结：在这项研究中，我们在前列腺癌的临床前模型中评估了新药 darolutamide。我们发现达洛鲁胺可以延缓恩杂鲁胺耐药性前列腺癌的生长，特别是在先前治疗后雄激素受体突变的细胞中。我们的数据支持在临床试验中进一步评估达洛鲁胺。 (c) 2017 年由 Elsevier B.V. 代表欧洲泌尿外科协会发布。
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.