Nguyen Holly M, Vessella Robert L, Morrissey Colm, Brown Lisha G, Coleman Ilsa M, Higano Celestia S, Mostaghel Elahe A, Zhang Xiaotun, True Lawrence D, Lam Hung-Ming, Roudier Martine, Lange Paul H, Nelson Peter S, Corey Eva
Department of Urology, University of Washington, Seattle, Washington.
Puget Sound Veteran Administration, Seattle, Washington.
Prostate. 2017 May;77(6):654-671. doi: 10.1002/pros.23313. Epub 2017 Feb 3.
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.
转移性前列腺癌是一种常见的致命疾病，目前尚无能够治愈或实现长期持久缓解的治疗方法。需要具有临床相关性的临床前模型来增进我们对这种恶性肿瘤生物学特性的了解，并评估可能提供有效治疗的新药物。我们的目标是建立并表征来自晚期前列腺癌（PC）的患者来源异种移植模型（PDXs），以研究其生物学特性并评估新的治疗方式。
从手术时获取的原发性前列腺癌或死亡时收集的转移灶中获得的晚期PC样本被植入免疫缺陷小鼠体内以建立PDXs。已建立的PDXs在体内进行传代培养。生成基因组、转录组和STR图谱。对体内雄激素剥夺和多西他赛的反应进行表征。
我们建立了多个PDXs（LuCaP系列），它们代表了该疾病在人类中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、由于MSH2/MSH6基因组畸变导致的高突变以及BRCA2缺失。PDX模型还表现出肿瘤内雄激素水平的差异。我们的体内结果显示，对于晚期PC的标准治疗方法雄激素剥夺和多西他赛，其反应存在异质性，这与患者对这些治疗的反应相似。
LuCaP PDX系列反映了人类去势抵抗性PC的多种分子组成，并允许对治疗反应和耐药性潜在机制进行假设驱动的因果研究。《前列腺》77: 654 - 671, 2017。© 2017作者。《前列腺》由威利期刊公司出版。
