In vivo imaging xenograft models for the evaluation of anti-brain tumor efficacy of targeted drugs.

Abstract

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.

• Authors: Kenji Kita, Sachiko Arai, Akihiro Nishiyama, Hirokazu Taniguchi, Koji Fukuda, Rong Wang, Tadaaki Yamada, Shinji Takeuchi, Shoichiro Tange, Atsushi Tajima, Mitsutoshi Nakada, Kazuo Yasumoto, Yoshiharu Motoo, Takashi Murakami, Seiji Yano
• Journal: Cancer medicine (Cancer Med) Vol. 6 Issue 12 Pg. 2972-2983 (Dec 2017) ISSN: 2045-7634 [Electronic] United States
• PMID: 29125233 (Publication Type: Comparative Study, Journal Article)
• Copyright: © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• HGF protein, human
• NTRK1 protein, human
• Protein Kinase Inhibitors
• Hepatocyte Growth Factor
• EGFR protein, human
• ErbB Receptors
• Receptor, trkA

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Biomarkers, Tumor (antagonists & inhibitors, genetics)
• Brain Neoplasms (diagnostic imaging, drug therapy, genetics, secondary)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• ErbB Receptors (antagonists & inhibitors, genetics)
• Female
• Hepatocyte Growth Factor (antagonists & inhibitors, genetics)
• Humans
• Mice, SCID
• Molecular Imaging (methods)
• Molecular Targeted Therapy
• Predictive Value of Tests
• Protein Kinase Inhibitors (pharmacology)
• Receptor, trkA (antagonists & inhibitors, genetics)
• Signal Transduction (drug effects)
• Time Factors
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays