In vivo imaging xenograft models for the evaluation of anti-brain tumor efficacy of targeted drugs.
In vivo imaging xenograft models for the evaluation of anti-brain tumor efficacy of targeted drugs.
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DOI：
10.1002/cam4.1255
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发表时间：
2017-12
期刊：
影响因子：
4
通讯作者：
Yano S
中科院分区：
文献类型：
--
作者：
Kita K;Arai S;Nishiyama A;Taniguchi H;Fukuda K;Wang R;Yamada T;Takeuchi S;Tange S;Tajima A;Nakada M;Yasumoto K;Motoo Y;Murakami T;Yano S
分子靶向药物通常对含有驱动癌基因（如EGFR、ALK和NTRK 1）的肿瘤有效。然而，携带这些癌基因的患者在治疗期间经常经历脑转移的进展。在这里，我们提出了一种使用人类癌细胞系的脑肿瘤体内成像模型，包括EGFR-L 858 R/T790 M-阳性H1975肺腺癌细胞，NUGC 4肝细胞生长因子（HGF）依赖性胃癌细胞和含有TPM 3-NTRK 1基因融合的KM 12 SM结直肠癌细胞。我们通过比较靶向药物在颅外模型中的作用来研究靶向药物的疗效。在体外，H1975细胞对第三代表皮生长因子受体抑制剂奥希替尼敏感。此外，HGF刺激NUGC 4细胞的增殖，这被具有抗MET活性的克唑替尼抑制。KM 12 SM细胞对原肌球蛋白相关激酶A抑制剂克唑替尼和恩曲替尼敏感。在体内H1975细胞模型中，奥希替尼可抑制脑肿瘤和皮下肿瘤的进展。此外，在体内NUGC 4细胞模型中，克唑替尼显著延迟了脑肿瘤和腹膜癌病的进展。有趣的是，在体内KM 12 SM细胞模型中，克唑替尼治疗延迟了肝转移的进展，但没有延迟脑肿瘤的进展。相反，使用恩曲替尼治疗可以延迟两种肿瘤类型的进展。因此，靶向药物对脑肿瘤的作用可能与颅外肿瘤的作用不同。此外，相同的多激酶抑制药物在含有不同驱动因子的脑肿瘤模型中可以显示不同的功效。因此，我们的脑肿瘤体内成像模型可能被证明是有用的临床前药物筛选对脑转移。
Molecular‐targeted drugs are generally effective against tumors containing driver oncogenes, such as EGFR,ALK, and NTRK1. However, patients harboring these oncogenes frequently experience a progression of brain metastases during treatment. Here, we present an in vivo imaging model for brain tumors using human cancer cell lines, including the EGFR‐L858R/T790M‐positive H1975 lung adenocarcinoma cells, the NUGC4 hepatocyte growth factor (HGF)‐dependent gastric cancer cells, and the KM12SM colorectal cancer cells containing the TPM3‐NTRK1 gene fusion. We investigated the efficacy of targeted drugs by comparison with their effect in extracranial models. In vitro, H1975 cells were sensitive to the third‐generation epidermal growth factor receptor inhibitor osimertinib. Moreover, HGF stimulated the proliferation of NUGC4 cells, that was inhibited by crizotinib, which has anti‐MET activity. KM12SM cells were sensitive to the tropomyosin‐related kinase‐A inhibitors crizotinib and entrectinib. In in vivo H1975 cell models, osimertinib inhibited the progression of both brain and subcutaneous tumors. Furthermore, in in vivo NUGC4 cell models, crizotinib remarkably delayed the progression of brain tumors, and that of peritoneal carcinomatosis. Interestingly, in in vivo KM12SM cell models, treatment with crizotinib delayed the progression of liver metastases, but not that of brain tumors. Conversely, treatment with entrectinib discernibly delayed the progression of both tumor types. Thus, the effect of targeted drugs against brain tumors can differ from the one reported in extracranial tumors. Moreover, the same multikinase inhibitory drug can display different efficacies in brain tumor models containing different drivers. Therefore, our in vivo imaging model for brain tumors may prove useful for preclinical drug screening against brain metastases.
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影响因子：
6.4
作者：
Matsumoto, Shingo;Takahashi, Kenji;Yokota, Jun
通讯作者：
Yokota, Jun
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Shaw, Alice T.
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De Braud FG
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Edwards, Martin P.
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MARTINZANCA, D;HUGHES, SH;BARBACID, M
通讯作者：
BARBACID, M