P1.03-032 In vivo Imaging Models for Preclinical Screening of Molecular Targeted Drugs against Brain Metastasis

Abstract

Molecular targeted drugs are generally effective on tumors with driver oncogene, including EGFR, ALK, and NTRK1. However, patients with these oncogenes frequently experience progression of brain metastasis during the targeted drug treatment. Thus, it is essential to establish more effective treatment for controlling brain metastasis. We established in vivo imaging brain tumor models by intracranial inoculation of human cancer cell lines, such as lung adenocarcinoma H1975 cells with EGFR-L858R and T790M mutations, HGF-dependent gastric cancer NUGC4 cells, and TPM3-NTRK1-fusion gene positive colorectal cancer KM12SM cells, in SCID mice. We investigated the activity of several molecular targeted drugs on cell proliferation of these cell lines in vitro. In addition, we evaluated the efficacy of these drugs on brain tumor models, comparing with extracranial tumor models. In vitro conditions, H1975 cells were sensitive to the 3rd generation EGFR inhibitor, osimertinib. HGF stimulated proliferation of gastric cancer NUGC4 cells, and the HGF-induced proliferation was inhibited by crizotinib, which has anti-MET activity, in a dose-dependent manner. KM12SM cells, which are the highly liver metastatic variant derived from TPM3-NTRK1 fusion gene positive colon cancer KM12C cells. KM12SM were sensitive to TRK-A inhibitors, crizotinib and entrectinib. In H1975-cell in vivo models, osimertinib (25mg/kg) inhibited the progression of both brain tumors and subcutaneous tumors. In NUGC4-cell in vivo models, crizotinib (50mg/kg) delayed the progression of brain tumors as well as peritoneal carcinomatosis, and prolonged the survival of the tumor bearing mice. In KM12SM-cell in vivo models, we evaluated the effect of crizotinib (50mg/kg) or entrectinib (15mg/kg) in the brain tumor model and liver metastasis model. Crizotinib treatment slightly delayed the progression of brain tumors but failed to prolong the survival of the recipient mice. Entrectinib treatment more discernibly delayed the progression of brain tumors and did prolong the survival. These results indicate that the effect of targeted drugs against brain tumors can be different from that against extracranial tumors. Our in vivo imaging brain tumor models may be useful for preclinical drug screening against brain metastasis.