Establishment of Patient-Derived Tumor Xenograft Models of Epithelial Ovarian Cancer for Preclinical Evaluation of Novel Therapeutics.
Establishment of Patient-Derived Tumor Xenograft Models of Epithelial Ovarian Cancer for Preclinical Evaluation of Novel Therapeutics.
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DOI：
10.1158/1078-0432.ccr-16-1237
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发表时间：
2017-03-01
期刊：
影响因子：
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通讯作者：
Drapkin R
中科院分区：
文献类型：
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作者：
Liu JF;Palakurthi S;Zeng Q;Zhou S;Ivanova E;Huang W;Zervantonakis IK;Selfors LM;Shen Y;Pritchard CC;Zheng M;Adleff V;Papp E;Piao H;Novak M;Fotheringham S;Wulf GM;English J;Kirschmeier PT;Velculescu VE;Paweletz C;Mills GB;Livingston DM;Brugge JS;Matulonis UA;Drapkin R
在美国，卵巢癌是妇科恶性肿瘤死亡的主要原因，具有高复发率和最终对细胞毒性化疗的耐药性。需要允许准确和可重复的靶点发现和验证的模型系统来支持这种疾病的进一步药物开发。临床注释的患者来源的异种移植物（PDX）模型由从经历临床程序的患者的腹水或胸膜液分离的肿瘤细胞产生。通过免疫组织化学和分子分析对模型进行表征。将每个PDX固定化以允许通过生物发光成像（BLI）对腹膜内肿瘤负荷进行可再现的体内评估。开发了CA 125和人LINE-1的血浆测定法，作为体内疾病负荷的次要试验。产生了14个临床注释和分子表征的卵巢PDX模型。荧光素化的PDX模型保留了对非荧光素化的PDX和原始患者肿瘤的保真度，如通过免疫组织化学、阵列CGH以及靶向和全外显子组测序分析所证明的。模型显示了特异性遗传改变和PI 3 K信号通路成员激活的多样性。可以通过BLI或血浆标志物可重复地监测纯化的PDX模型对标准护理疗法的响应。我们描述了14个临床注释和分子表征的荧光素化卵巢PDX模型的建立，其中可以通过标准且可重复的方法跟踪腹腔内空间的原位肿瘤负荷。该集合非常适合作为概念验证有效性和生物标志物研究以及验证卵巢癌新治疗策略的平台。
Ovarian cancer is the leading cause of death from gynecologic malignancy in the United States, with high rates of recurrence and eventual resistance to cytotoxic chemotherapy. Model systems that allow for accurate and reproducible target discovery and validation are needed to support further drug development in this disease. Clinically-annotated patient-derived xenograft (PDX) models were generated from tumor cells isolated from the ascites or pleural fluid of patients undergoing clinical procedures. Models were characterized by immunohistochemistry and by molecular analyses. Each PDX was luciferized to allow for reproducible in vivo assessment of intraperitoneal tumor burden by bioluminescent imaging (BLI). Plasma assays for CA125 and human LINE-1 were developed as secondary tests of in vivo disease burden. 14 clinically annotated and molecularly characterized luciferized ovarian PDX models were generated. Luciferized PDX models retain fidelity to both the non-luciferized PDX and the original patient tumor, as demonstrated by immunohistochemistry, array CGH, and targeted and whole-exome sequencing analyses. Models demonstrated diversity in specific genetic alterations and activation of PI3K signaling pathway members. Response of luciferized PDX models to standard of care therapy could be reproducibly monitored by BLI or plasma markers. We describe the establishment of a collection of 14 clinically annotated and molecularly characterized luciferized ovarian PDX models in which orthotopic tumor burden in the intraperitoneal space can be followed by standard and reproducible methods. This collection is well-suited as a platform for proof-of-concept efficacy and biomarker studies and for validation of novel therapeutic strategies in ovarian cancer.