LuCaP Prostate Cancer Patient-Derived Xenografts Reflect the Molecular Heterogeneity of Advanced Disease an--d Serve as Models for Evaluating Cancer Therapeutics.
LuCaP Prostate Cancer Patient-Derived Xenografts Reflect the Molecular Heterogeneity of Advanced Disease an--d Serve as Models for Evaluating Cancer Therapeutics.
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DOI：
10.1002/pros.23313
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发表时间：
2017-05
期刊：
影响因子：
--
通讯作者：
Corey E
中科院分区：
文献类型：
--
作者：
Nguyen HM;Vessella RL;Morrissey C;Brown LG;Coleman IM;Higano CS;Mostaghel EA;Zhang X;True LD;Lam HM;Roudier M;Lange PH;Nelson PS;Corey E
转移性前列腺癌是一种常见且致命的疾病，目前尚无治愈或长期持久缓解的治疗方法。需要临床相关的临床前模型来增加我们对这种恶性肿瘤生物学的理解，并评估可能提供有效治疗的新药物。我们的目的是建立和表征晚期前列腺癌（PC）患者来源的异种移植物（PDXs），以研究生物学和评估新的治疗方式。从手术中获得的原发性前列腺癌或死亡时收集的转移瘤中获得的晚期前列腺癌样本被植入免疫功能低下的小鼠体内以建立pdx。建立的pdx在体内繁殖。生成基因组、转录组和STR谱。体内对雄激素剥夺和多西紫杉醇的反应进行了表征。我们建立了多个pdx （LuCaP系列），它们代表了人类疾病的主要基因组和表型特征，包括雄激素受体扩增、PTEN缺失、TP53缺失和突变、RB1缺失、TMPRSS2‐ERG重排、SPOP突变、由MSH2/MSH6基因组畸变引起的高突变和BRCA2缺失。PDX模型也显示出肿瘤内雄激素水平的变化。我们的体内研究结果显示，对雄激素剥夺和多西他赛（晚期前列腺癌的标准治疗）的反应存在异质性，与患者对这些治疗的反应相似。LuCaP PDX系列反映了人类去势抗性PC的不同分子组成，并允许对治疗反应和抗性机制进行假设驱动的因果研究。《中华医学会杂志》，2017。©2017作者。由Wiley期刊公司出版的前列腺。
Metastatic prostate cancer is a common and lethal disease for which there are no therapies that produce cures or long‐term durable remissions. Clinically relevant preclinical models are needed to increase our understanding of biology of this malignancy and to evaluate new agents that might provide effective treatment. Our objective was to establish and characterize patient‐derived xenografts (PDXs) from advanced prostate cancer (PC) for investigation of biology and evaluation of new treatment modalities. Samples of advanced PC obtained from primary prostate cancer obtained at surgery or from metastases collected at time of death were implanted into immunocompromised mice to establish PDXs. Established PDXs were propagated in vivo. Genomic, transcriptomic, and STR profiles were generated. Responses to androgen deprivation and docetaxel in vivo were characterized. We established multiple PDXs (LuCaP series), which represent the major genomic and phenotypic features of the disease in humans, including amplification of androgen receptor, PTEN deletion, TP53 deletion and mutation, RB1 loss, TMPRSS2‐ERG rearrangements, SPOP mutation, hypermutation due to MSH2/MSH6 genomic aberrations, and BRCA2 loss. The PDX models also exhibit variation in intra‐tumoral androgen levels. Our in vivo results show heterogeneity of response to androgen deprivation and docetaxel, standard therapies for advanced PC, similar to the responses of patients to these treatments. The LuCaP PDX series reflects the diverse molecular composition of human castration‐resistant PC and allows for hypothesis‐driven cause‐and‐effect studies of mechanisms underlying treatment response and resistance. Prostate 77: 654–671, 2017. © 2017 The Authors. The Prostate Published by Wiley Periodicals, Inc.