DDIS-10. TARGETING HGF/MET IN GBM BY RESTORING SPINT2 FUNCTION

Glioblastoma (GBM) represents the most lethal form of primary glioma and not incurable with currently available surgical, radiation and chemotherapeutic modalities. Intensive molecular characterization of GBM has revealed a rich inter-tumoral diversity of molecular aberrations indicating the promise of personalized targeted therapies. In our previous study, we identified SPINT2 (Serine Protease Inhibitor, Kunitz Type, 2) from an unbiased promoter hypermethylation screen as one of the top cancer-related genes epigenetically downregulated by CpG island methylation in GBM. SPINT2 encodes a transmembrane glycoprotein that physiologically inhibits a broad spectrum of serine proteases including HGF activator (HGFA) and matriptase. Both HGFA and matriptase, often upregulated in a variety of tumors, are major physiological proteases proteolytically activating HGF/MET signaling. Analysis of TCGA indicates that matriptase is ubiquitously overexpressed in GBM in addition to SPINT2 down-regulation. Thus, the imbalanced activity of these serine proteases is presumably to enhance MET activation in the GBM exhibiting MET and HGF co-expression. Building on our prior data showing that SPINT2 re-expression restricted the growth and migration of glioma cells via down-regulating MET signaling, in vitro treatment with commercially available recombinant SPINT2 strongly suppressed MET signaling as well as glioma cell migration. We also show that SPINT2 re-expression suppressed glioma tumor growth in vivo and prolonged the survival of mice bearing intracranial tumors. Using a series of selective rationally designed serine protease inhibitors of HGFA, matriptase and hepsin, we found that these inhibitors could mimic SPINT2 activity by suppressing MET activation resulting in decreased tumor cell proliferation and anchorage-independent growth. In summary, we provide evidence that targeting imbalanced activity of HGF-activating serine proteases potentially serves as an innovative MET-targeting therapeutic strategy for GBM.