MerTK as a therapeutic target in glioblastoma.

Autor:	Wu J; Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Frady LN; Lineberger Comprehensive Cancer Center.; Department of Neurosurgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina., Bash RE; Lineberger Comprehensive Cancer Center.; Division of Neuropathology, Department of Pathology and Laboratory Medicine., Cohen SM; Division of Neuropathology, Department of Pathology and Laboratory Medicine., Schorzman AN; Division of Pharmacotherapy and Experimental Therapeutics, Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, North Carolina., Su YT; Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Irvin DM; Lineberger Comprehensive Cancer Center., Zamboni WC; Lineberger Comprehensive Cancer Center.; Division of Pharmacotherapy and Experimental Therapeutics, Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, North Carolina., Wang X; Division of Pharmacotherapy and Experimental Therapeutics, Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, North Carolina., Frye SV; Division of Pharmacotherapy and Experimental Therapeutics, Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, North Carolina., Ewend MG; Lineberger Comprehensive Cancer Center.; Department of Neurosurgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina., Sulman EP; Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas., Gilbert MR; Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Earp HS; Lineberger Comprehensive Cancer Center., Miller CR; Lineberger Comprehensive Cancer Center.; Division of Neuropathology, Department of Pathology and Laboratory Medicine.; Department of Neurology and Neurosciences Center.
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2018 Jan 10; Vol. 20 (1), pp. 92-102.
DOI:	10.1093/neuonc/nox111
Abstrakt:	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. (Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.)
Databáze:	MEDLINE
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