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Modeling acquired resistance to the second-generation androgen receptor antagonist enzalutamide in the TRAMP model of prostate cancer.
Cancer Research ( IF 11.2 ) Pub Date : 2020-04-01 , DOI: 10.1158/0008-5472.can-18-3637
Marianna Cerasuolo 1 , Federica Maccarinelli 2 , Daniela Coltrini 2 , Ali Mokhtar Mahmoud 3 , Viviana Marolda 3 , Gaia Cristina Ghedini 2 , Sara Rezzola 2 , Arianna Giacomini 2 , Luca Triggiani 4 , Magdalena Kostrzewa 3 , Roberta Verde 3 , Debora Paris 3 , Dominique Melck 3 , Marco Presta 2 , Alessia Ligresti 3 , Roberto Ronca 2
Affiliation  

Enzalutamide (MDV3100) is a potent second-generation androgen receptor antagonist approved for the treatment of castration-resistant prostate cancer (CRPC) in chemotherapy-naïve as well as in patients previously exposed to chemotherapy. However, resistance to enzalutamide and enzalutamide withdrawal syndrome have been reported. Thus, reliable and integrated preclinical models are required to elucidate the mechanisms of resistance and to assess therapeutic settings that may delay or prevent the onset of resistance. In this study, the prostate cancer (PCa) multistage murine model TRAMP and TRAMP-derived cells have been used to extensively characterize in vitro and in vivo the response and resistance to enzalutamide. The therapeutic profile as well as the resistance onset were characterized and a multiscale stochastic mathematical model was proposed to link the in vitro and in vivo evolution of PCa. The model showed that all therapeutic strategies that use enzalutamide result in the onset of resistance. The model also showed that combination therapies can delay the onset of resistance to enzalutamide, and in the best scenario, can eliminate the disease. These results set the basis for the exploitation of this "TRAMP-based platform" to test novel therapeutic approaches and build further mathematical models of combination therapies to treat PCa and CRPC.

中文翻译:

在前列腺癌的TRAMP模型中对第二代雄激素受体拮抗剂enzalutamide的获得性抗性进行建模。

Enzalutamide(MDV3100)是一种有效的第二代雄激素受体拮抗剂,已被批准用于初次化疗以及以前接受过化疗的患者的去势抵抗性前列腺癌(CRPC)。然而,已经报道了对恩杂鲁胺和恩杂鲁胺戒断综合症的抵抗力。因此,需要可靠且综合的临床前模型来阐明耐药性机制并评估可能延迟或预防耐药性发作的治疗环境。在这项研究中,前列腺癌(PCa)多阶段鼠模型TRAMP和TRAMP衍生的细胞已被广泛用于体外和体内表征对enzalutamide的反应和抗性。表征了治疗概况以及耐药性发作,并提出了一种多尺度随机数学模型来联系PCa的体内和体外进化。该模型表明,使用恩杂鲁胺的所有治疗策略均会导致耐药性发作。该模型还显示,联合疗法可以延迟对恩杂鲁胺的耐药性发作,并且在最佳情况下可以消除疾病。这些结果为开发这种“基于TRAMP的平台”以测试新颖的治疗方法奠定了基础,并为治疗PCa和CRPC的联合治疗建立了进一步的数学模型。该模型还表明,联合疗法可以延迟对恩杂鲁胺的耐药性发作,并且在最佳情况下可以消除疾病。这些结果为开发这种“基于TRAMP的平台”以测试新颖的治疗方法奠定了基础,并为治疗PCa和CRPC的联合治疗建立了进一步的数学模型。该模型还显示,联合疗法可以延迟对恩杂鲁胺的耐药性发作,并且在最佳情况下可以消除疾病。这些结果为开发这种“基于TRAMP的平台”以测试新颖的治疗方法奠定了基础,并为治疗PCa和CRPC的联合治疗建立了进一步的数学模型。
更新日期:2020-04-03
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