Characterization and validation of potential therapeutic targets based on the molecular signature of patient-derived xenografts in gastric cancer.
Characterization and validation of potential therapeutic targets based on the molecular signature of patient-derived xenografts in gastric cancer.
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DOI：
10.1186/s13045-018-0563-y
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发表时间：
2018-02-13
影响因子：
28.5
通讯作者：
Shen L
中科院分区：
文献类型：
--
作者：
Chen Z;Huang W;Tian T;Zang W;Wang J;Liu Z;Li Z;Lai Y;Jiang Z;Gao J;Shen L
具有明确分子特征的患者来源的异种移植（PDX）模型是开发新型靶向药物的有吸引力的临床前模型。在这里，我们基于晚期胃癌 (AGC) 的特征性 PDX 模型来分析和探索潜在的治疗靶点。通过靶向二代测序、原位杂交和免疫组织化学分析了来自 AGC 患者的 50 个 PDX 模型的基因组变异和分子谱。在 PDX 模型中研究了几种靶向药物的抗肿瘤活性。此外，还探索了反应生物标志物。每个 PDX 模型都有各自的组织病理学和分子特征，MAPK、ErbB、VEGF、mTOR 和细胞周期信号通路的反复改变是这些 PDX 模型中的主要事件。本研究选择并验证了几个潜在的药物靶点，例如 EGFR、MET 和 CCNE1。沃利替尼在 MET 和磷酸化 MET (pMET) 过表达的 PDX 模型中表现出强大的抗肿瘤活性。 EGFR 单克隆抗体 BK011 和西妥昔单抗在具有 EGFR 扩增的 PDX 模型中抑制肿瘤生长。阿法替尼通过 EGFR 扩增、EGFR 过表达或 HER2 扩增抑制 PDX 模型中的肿瘤生长。阿帕替尼在微血管密度高的 PDX 模型中更敏感。 CDK1/2/9抑制剂AZD5438在两个CCNE1拷贝数较高的模型中具有优异的抗肿瘤活性。具有明确分子特征的 PDX 模型对于靶向药物的临床前研究非常有用，其结果应在使用 PDX 模型的更大型研究或临床试验中得到验证。本文的在线版本 (10.1186/s13045-018-0563-y) 包含补充材料，可供授权用户使用。
Patient-derived xenograft (PDX) models with definite molecular signature are attractive preclinical models for development of novel targeted drugs. Here, we profiled and explored potential therapeutic targets based on characterized PDX models for advanced gastric cancer (AGC). The genomic variation and molecular profile of 50 PDX models from AGC patients were analyzed by targeted next-generation sequencing, in situ hybridization, and immunohistochemistry. The antitumor activities of several targeted drugs were investigated in the PDX models. Furthermore, response biomarkers were explored. Each PDX model had individual histopathological and molecular features, and recurrent alterations in the MAPK, ErbB, VEGF, mTOR, and cell cycle signaling pathways were major events in these PDX models. Several potential drug targets, such as EGFR, MET, and CCNE1, were selected and validated in this study. Volitinib demonstrated strong antitumor activity in PDX models with MET and phosphorylated MET (pMET) overexpression. The EGFR monoclonal antibodies BK011 and cetuximab inhibited tumor growth in a PDX model with EGFR amplification. Afatinib inhibited tumor growth in the PDX models with EGFR amplification, EGFR overexpression, or HER2 amplification. Apatinib was more sensitive in the PDX models with high microvessel density. The CDK1/2/9 inhibitor AZD5438 had superior anti-tumor activity in two models with higher copy number of CCNE1. PDX models with defined molecular signature are useful for preclinical studies with targeted drugs, and the results should be validated in larger studies with PDX models or in clinical trials. The online version of this article (10.1186/s13045-018-0563-y) contains supplementary material, which is available to authorized users.
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影响因子：
3.8
作者：
Luber B;Deplazes J;Keller G;Walch A;Rauser S;Eichmann M;Langer R;Höfler H;Hegewisch-Becker S;Folprecht G;Wöll E;Decker T;Endlicher E;Lorenzen S;Fend F;Peschel C;Lordick F
通讯作者：
Lordick F
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
--
作者：
Derks S;Liao X;Chiaravalli AM;Xu X;Camargo MC;Solcia E;Sessa F;Fleitas T;Freeman GJ;Rodig SJ;Rabkin CS;Bass AJ
通讯作者：
Bass AJ
影响因子：
11.5
作者：
Lee, Hye Won;Lee, Jung-il;Nam, Do-Hyun
通讯作者：
Nam, Do-Hyun
影响因子：
8.8
作者：
Lee, H. E.;Kim, M. A.;Lee, H. S.;Jung, E-J;Yang, H-K;Lee, B. L.;Bang, Y-J;Kim, W. H.
通讯作者：
Kim, W. H.