MerTK as a therapeutic target in glioblastoma.

Abstract

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.

• Authors: Jing Wu, Lauren N Frady, Ryan E Bash, Stephanie M Cohen, Allison N Schorzman, Yu-Ting Su, David M Irvin, William C Zamboni, Xiaodong Wang, Stephen V Frye, Matthew G Ewend, Erik P Sulman, Mark R Gilbert, H Shelton Earp, C Ryan Miller
• Journal: Neuro-oncology (Neuro Oncol) Vol. 20 Issue 1 Pg. 92-102 (01 10 2018) ISSN: 1523-5866 [Electronic] England
• PMID: 28605477 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 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.

Chemical References

• Piperazines
• UNC2025
• MERTK protein, human
• Mertk protein, mouse
• Receptor Protein-Tyrosine Kinases
• c-Mer Tyrosine Kinase
• Adenine

Topics

• Adenine (analogs & derivatives, therapeutic use)
• Animals
• Brain Neoplasms (pathology, therapy)
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic (drug effects)
• Glioblastoma (pathology, therapy)
• Humans
• Mice
• Microglia (drug effects, metabolism)
• Piperazines (therapeutic use)
• Receptor Protein-Tyrosine Kinases (genetics)
• c-Mer Tyrosine Kinase (drug effects, genetics)