Preclinical evaluation of biomarkers for response monitoring to the MET inhibitor BAY-853474

Autor:	Thomas Krahn, Tanja Rose, Kirsten Steiner-Hahn, Elke Schmid, Monika Klotz, David Henderson, Jenny Laube, Lars Roese, Oliver von Ahsen
Rok vydání:	2012
Předmět:	Vascular Endothelial Growth Factor A Health Toxicology and Mutagenesis Clinical Biochemistry Mice Nude Antineoplastic Agents Context (language use) Biochemistry Receptor tyrosine kinase Metastasis Mice chemistry.chemical_compound Cell Line Tumor Neoplasms Biomarkers Tumor medicine Animals Humans Interleukin 8 Phosphorylation biology Hepatocyte Growth Factor Interleukin-8 Cancer Proto-Oncogene Proteins c-met medicine.disease Xenograft Model Antitumor Assays Tumor Burden Enzyme Activation Vascular endothelial growth factor chemistry Case-Control Studies Immunology Cancer research biology.protein Biomarker (medicine) Female Hepatocyte growth factor Protein Processing Post-Translational medicine.drug
Zdroj:	Biomarkers. 17:325-335
ISSN:	1366-5804 1354-750X
DOI:	10.3109/1354750x.2012.670865
Popis:	The receptor tyrosine kinase MET contributes to a wide range of biological activities, including survival, proliferation, and metastasis, which play an important role in cancer progression. MET is frequently overexpressed or amplified in a range of malignancies. Therefore, MET is an attractive therapeutic target for treatment of cancer. BAY-853474 is a novel specific MET inhibitor highly effective in preclinical tumor models.For response monitoring in clinical studies, soluble plasma biomarkers are the most convenient and least invasive choice. Therefore, we sought to identify such biomarkers in xenograft models.We show that BAY-853474 reduces the tumor burden in U87MG glioblastoma, NCI-H1993 nonsmall cell lung cancer, and HS746T gastric cancer xenograft models. We demonstrate that the dose dependence is reflected by inhibition of MET phosphorylation and that the soluble plasma biomarkers hepatocyte growth factor, vascular endothelial growth factor, and interleukin-8 as well as the MET-ectodomain can be used to monitor the tumor size and response to treatment. Clinical samples, however, show only moderately elevated levels of these biomarker candidates in cancer patients even with MET amplification. We, therefore, established an immunohistochemistry (IHC) protocol to detect MET phosphorylation that is suitable to monitor the effect of BAY-853474 in tumor biopsies.IHC-based analysis of target phosphorylation in tumor biopsies is recommended in addition to testing plasma biomarkers for response monitoring.
Databáze:	OpenAIRE
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