Wang Haiyong, Lu Jun, Tang Jian, Chen Shitu, He Kuifeng, Jiang Xiaoxia, Jiang Weiqin, Teng Lisong
Department of surgical oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang Province, China.
Department of oncology, Jiaxing First Hospital, Jiaxing, 314000, Zhejiang Province, China.
BMC Cancer. 2017 Mar 14;17(1):191. doi: 10.1186/s12885-017-3177-9.
Targeted therapies are emerging treatment options for gastric cancer (GC). Patient-derived tumor xenograft(PDX) models of GC closely retain the features of the original clinical cancer, offering a powerful tool for preclinical drug efficacy testing. This study aimed to establish PDX GC models, and explore therapeutics targeting Her2, MET(cMet), and FGFR2, which may assist doctor to select the proper target therapy for selected patients.
GC tissues from 32 patients were collected and implanted into immuno-deficient mice. Using immunohistochemistry(IHC) and fluorescent in-situ hybridization (FISH), protein levels and/or gene amplification of Her2, cMet and FGFR2 in those tissues were assessed. Finally, anti-tumor efficacy was tested in the PDX models using targeted inhibitors.
A total of 9 passable PDX models were successfully established from 32 gastric cancer xenograft donors, consisting of HER2,cMet and FGFR2 alterations with percentages of 4(12.5%), 8(25.0%) and 1(3.1%) respectively. Crizotinib and AZD4547 exerted marked antitumor effects exclusively in PDX models with cMet (G30,G31) and FGFR2(G03) amplification. Interestingly, synergistic antitumor activity was observed in G03 (FGFR2-amplifed and cMet non-amplified but IHC [2+]) with simultaneous treatment with Crizotinib and ADZ4547 at day 30 post-treatment. Further in vitro biochemistry study showed a synergistic inhibition of the MAPK/ERK pathway. HER2,cMet and FGFR2 alterations were found in 17 (10.4%), 32(19.6%) and 6(3.7%) in a group of 163 GC patients, and cMet gene amplification or protein overexpression(IHC 3+) was associated with poor prognosis.
These PDX GC models provide an ideal platform for drug screening and evaluation. GC patients with positive cMet or FGFR2 gene amplification may potentially benefit from cMet or FGFR2 targeted therapies or combined targeted therapy.
靶向治疗是胃癌（GC）新兴的治疗选择。患者来源的胃癌肿瘤异种移植（PDX）模型紧密保留了原始临床癌症的特征，为临床前药物疗效测试提供了强大工具。本研究旨在建立PDX胃癌模型，并探索针对Her2、MET（cMet）和FGFR2的治疗方法，这可能有助于医生为特定患者选择合适的靶向治疗。
收集32例患者的胃癌组织并植入免疫缺陷小鼠体内。使用免疫组织化学（IHC）和荧光原位杂交（FISH）评估这些组织中Her2、cMet和FGFR2的蛋白水平和/或基因扩增情况。最后，在PDX模型中使用靶向抑制剂测试抗肿瘤疗效。
从32例胃癌异种移植供体中成功建立了9个合格的PDX模型，其中HER2、cMet和FGFR2改变的模型分别有4个（12.5%）、8个（25.0%）和1个（3.1%）。克唑替尼和AZD4547仅在cMet（G30、G31）和FGFR2（G03）扩增的PDX模型中发挥显著的抗肿瘤作用。有趣的是，在治疗后第30天同时使用克唑替尼和ADZ4547治疗时，在G03（FGFR2扩增且cMet未扩增但IHC[2+]）模型中观察到协同抗肿瘤活性。进一步的体外生物化学研究显示对MAPK/ERK途径有协同抑制作用。在一组163例胃癌患者中，发现HER2、cMet和FGFR2改变的分别有17例（10.4%）、32例（19.6%）和6例（3.7%），且cMet基因扩增或蛋白过表达（IHC 3+）与预后不良相关。
这些PDX胃癌模型为药物筛选和评估提供了理想平台。cMet或FGFR2基因扩增阳性的胃癌患者可能从cMet或FGFR2靶向治疗或联合靶向治疗中潜在获益。
