MerTK as a therapeutic target in glioblastoma
| Autor: | Jing Wu, Matthew G. Ewend, Yu Ting Su, Erik P. Sulman, Ryan E. Bash, William C. Zamboni, David M. Irvin, H. Shelton Earp, Lauren N. Frady, Mark R. Gilbert, Allison N. Schorzman, C. Ryan Miller, Stephen V. Frye, Xiaodong Wang, Stephanie M. Cohen |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Pathology medicine.medical_specialty Biology Piperazines Mice 03 medical and health sciences In vivo Cell Line Tumor Glioma medicine Animals Humans Bioluminescence imaging Efferocytosis c-Mer Tyrosine Kinase Microglia Brain Neoplasms CD68 Adenine Receptor Protein-Tyrosine Kinases MERTK medicine.disease Gene Expression Regulation Neoplastic MERTK Gene 030104 developmental biology medicine.anatomical_structure Oncology Basic and Translational Investigations Neurology (clinical) Glioblastoma |
| Zdroj: | Neuro-Oncology. 20:92-102 |
| ISSN: | 1523-5866 1522-8517 |
| Popis: | Background Glioma-associated macrophages and microglia (GAMs) are components of the glioblastoma (GBM) microenvironment that express MerTK, a receptor tyrosine kinase that triggers efferocytosis and can suppress innate immune responses. The aim of the study was to define MerTK as a therapeutic target using an orally bioavailable inhibitor, UNC2025. Methods We examined MerTK expression in tumor cells and macrophages in matched patient GBM samples by double-label immunohistochemistry. UNC2025-induced MerTK inhibition was studied in vitro and in vivo. Results MerTK/CD68+ macrophages increased in recurrent tumors while MerTK/glial fibrillary acidic protein-positive tumor cells did not. Pharmacokinetic studies showed high tumor exposures of UNC2025 in a syngeneic orthotopic allograft mouse GBM model. The same model mice were randomized to receive vehicle, daily UNC2025, fractionated external beam radiotherapy (XRT), or UNC2025/XRT. Although median survival (21, 22, 35, and 35 days, respectively) was equivalent with or without UNC2025, bioluminescence imaging (BLI) showed significant growth delay with XRT/UNC2025 treatment and complete responses in 19%. The responders remained alive for 60 days and showed regression to 1%-10% of pretreatment BLI tumor burden; 5 of 6 were tumor free by histology. In contrast, only 2% of 98 GBM mice of the same model treated with XRT survived 50 days and none survived 60 days. UNC2025 also reduced CD206+ macrophages in mouse tumor samples. Conclusions These results suggest that MerTK inhibition combined with XRT has a therapeutic effect in a subset of GBM. Further mechanistic studies are warranted. |
| Databáze: | OpenAIRE |
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