Fichtner Iduna, Rolff Jana, Soong Richie, Hoffmann Jens, Hammer Stefanie, Sommer Anette, Becker Michael, Merk Johannes
Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany.
Clin Cancer Res. 2008 Oct 15;14(20):6456-68. doi: 10.1158/1078-0432.CCR-08-0138.
It was the aim of our study to establish an extensive panel of non-small cell lung cancer (NSCLC) xenograft models useful for the testing of novel compounds and for the identification of biomarkers.
Starting from 102 surgical NSCLC specimens, which were obtained from primarily diagnosed patients with early-stage tumors (T(2)/T(3)), 25 transplantable xenografts were established and used for further investigations.
Early passages of the NSCLC xenografts revealed a high degree of similarity with the original clinical tumor sample with regard to histology, immunohistochemistry, as well as mutation status. The chemotherapeutic responsiveness of the xenografts resembled the clinical situation in NSCLC with tumor shrinkage obtained with paclitaxel (4 of 25), gemcitabine (3 of 25), and carboplatin (3 of 25) and lower effectiveness of etoposide (1 of 25) and vinorelbine (0 of 11). Twelve of 25 NSCLC xenografts were >50% growth inhibited by the anti-epidermal growth factor receptor (EGFR) antibody cetuximab and 6 of 25 by the EGFR tyrosine kinase inhibitor erlotinib. The response to the anti-EGFR therapies did not correlate with mutations in the EGFR or p53, but there was a correlation of K-ras mutations and erlotinib resistance. Protein analysis revealed a heterogeneous pattern of expression. After treatment with cetuximab, we observed a down-regulation of EGFR in 2 of 6 sensitive xenograft models investigated but never in resistant models.
An extensive panel of patient-derived NSCLC xenografts has been established. It provides appropriate models for testing marketed as well as novel drug candidates. Additional expression studies allow the identification of stratification biomarkers for targeted therapies.
我们研究的目的是建立一个广泛的非小细胞肺癌（NSCLC）异种移植模型库，用于测试新型化合物和鉴定生物标志物。
从102例手术切除的NSCLC标本开始，这些标本取自初诊为早期肿瘤（T(2)/T(3)）的患者，建立了25个可移植的异种移植物并用于进一步研究。
NSCLC异种移植物的早期传代在组织学、免疫组织化学以及突变状态方面与原始临床肿瘤样本高度相似。异种移植物的化疗反应性类似于NSCLC的临床情况，紫杉醇（25例中有4例）、吉西他滨（25例中有3例）和卡铂（25例中有3例）可使肿瘤缩小，而依托泊苷（25例中有1例）和长春瑞滨（11例中有0例）的疗效较低。25个NSCLC异种移植物中有12个被抗表皮生长因子受体（EGFR）抗体西妥昔单抗抑制生长>50%，25个中有6个被EGFR酪氨酸激酶抑制剂厄洛替尼抑制生长。对抗EGFR治疗的反应与EGFR或p53的突变无关，但K-ras突变与厄洛替尼耐药相关。蛋白质分析显示表达模式存在异质性。在用西妥昔单抗治疗后，我们在所研究的6个敏感异种移植模型中有2个观察到EGFR下调，但在耐药模型中从未观察到。
已建立了一个广泛的患者来源的NSCLC异种移植模型库。它为测试上市药物以及新型候选药物提供了合适的模型。额外的表达研究有助于鉴定靶向治疗的分层生物标志物。
