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
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 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 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.
Conclusion and Implications : MAGL inhibition may represent a
therapeutic approach to reduce TNBC growth and metastasis in brain by
inhibiting the BBB permeability changes.