Targeting Monoacylglycerol Lipase in Triple-Negative Breast Cancer
Reduced Tumor-Associated Inflammation and Decreased Colonization in the
Brain
Abstract
Background and Purpose: While the prevalence of breast cancer metastasis
in the brain is significantly higher in triple-negative breast cancers
(TNBCs), there is a lack of novel and/or improved therapeutic approaches
for these patients. Here, we explore the role of monoacylglycerol lipase
(MAGL) in tumor growth and colonization in the brain. Experimental
Approach: MAGL inhibitor AM9928 was selected for these studies due to
its high specificity (hMAGL IC50 = 9nM). The effects of AM9928 on TNBC
adhesion and transmigration across a 3D culture with human brain
microvascular endothelial cells (BMECs) and the secretion of
chemokines/cytokines were examined. The effects of AM9928 on TNBC tumor
growth and tumor colonization in vivo in the brain were performed using
TNBC mice models. Key Results: The residence time based on NMR time
course data for AM9928 is 46 hours indicating prolonged pharmacodynamic
effect. AM9928 blocked TNBC cell adhesion and transmigration across
HBMECs in a 3D culture. AM9928 inhibited the secretion of IL-6, IL-8,
and VEGF-A from TNBC cells and from HBMECs cultures exposed to
TNBC-derived exosomes. Using in vivo studies of syngeneic GFP-4T1-BrM5
mammary tumor cells, AM9928 inhibited tumor growth in the mammary fat
pads and attenuated blood-brain barrier (BBB) permeability changes,
resulting in reduced TNBC colonization in the brain. Together, these
results demonstrate inhibition of TNBC tumor growth and brain
colonization by AM9928 and support the potential clinical application of
MAGL inhibitors as a novel treatment for TNBC.