Patient-Derived Xenografts from Non-Small Cell Lung Cancer Brain Metastases Are Valuable Translational Platforms for the Development of Personalized Targeted Therapy
Patient-Derived Xenografts from Non-Small Cell Lung Cancer Brain Metastases Are Valuable Translational Platforms for the Development of Personalized Targeted Therapy
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DOI：
10.1158/1078-0432.ccr-14-1589
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发表时间：
2015-03-01
影响因子：
11.5
通讯作者：
Nam, Do-Hyun
中科院分区：
文献类型：
--
作者：
Lee, Hye Won;Lee, Jung-il;Nam, Do-Hyun
目的：非小细胞肺癌（NSCLC）远处转移的发病率日益增加，这表明迫切需要新的治疗方式。脑转移在NSCLC中特别常见，对临床预后有严重的不良影响。尽管NSCLC的分子异质性和各种靶向药物的可用性表明了针对此类脑转移瘤的个性化治疗方法，但需要进一步开发适当的临床前模型来验证这些策略。实验设计：我们使用NSCLC脑转移瘤手术样本建立了患者来源的异种移植物（PDX），并阐明了其可能的临床前和临床个性化治疗的意义。NSCLC脑转移瘤（n = 34）的PDX成功建立率显著高于原发性标本（n = 64; 74% vs. 23%）。来源于NSCLC脑转移瘤的PDX重现了相应亲本肿瘤的病理、遗传和功能特性。此外，在无血清条件下从异种移植物体外建立的肿瘤球保持其体内脑转移潜能。随后可以使用这些来自脑转移瘤的NSCLC PDX在体外筛选对20种靶向药物的不同表型和分子反应。尽管原发性NSCLC的PDX建立受到组织学亚型、临床侵袭性和遗传改变状态的显著影响，但脑转移瘤始终表现出足够的体内肿瘤摄取率和体外肿瘤球形成能力，无论临床和分子条件如何。因此，我们认为，来自NSCLC脑转移瘤的PDX可能更好地代表异质性晚期NSCLC人群，并可用作临床前模型，以满足未满足的要求。临床需求，如个性化治疗的药物筛选。（C）2014年AACR。
Purpose: The increasing prevalence of distant metastases from non-small cell lung cancer (NSCLC) indicates an urgent need for novel therapeutic modalities. Brain metastasis is particularly common in NSCLC, with severe adverse effects on clinical prognosis. Although the molecular heterogeneity of NSCLC and availability of various targeted agents suggest personalized therapeutic approaches for such brain metastases, further development of appropriate preclinical models is needed to validate the strategies.Experimental Design: We established patient-derived xenografts (PDX) using NSCLC brain metastasis surgical samples and elucidated their possible preclinical and clinical implications for personalized treatment.Results: NSCLC brain metastases (n = 34) showed a significantly higher successful PDX establishment rate than primary specimens (n = 64; 74% vs. 23%). PDXs derived from NSCLC brain metastases recapitulated the pathologic, genetic, and functional properties of corresponding parental tumors. Furthermore, tumor spheres established in vitro from the xenografts under serum-free conditions maintained their in vivo brain metastatic potential. Differential phenotypic and molecular responses to 20 targeted agents could subsequently be screened in vitro using these NSCLC PDXs derived from brain metastases. Although PDX establishment from primary NSCLCs was significantly influenced by histologic subtype, clinical aggressiveness, and genetic alteration status, the brain metastases exhibited consistently adequate in vivo tumor take rate and in vitro tumor sphere formation capacity, regardless of clinical and molecular conditions.Conclusions: Therefore, PDXs from NSCLC brain metastases may better represent the heterogeneous advanced NSCLC population and could be utilized as preclinical models to meet unmet clinical needs such as drug screening for personalized treatments. (C)2014 AACR.