Activated Matriptase (actM) as a Cancer Treatment
Matriptase serine protease activation is tightly regulated by complex formation with hepatocyte growth factor activator inhibitor-1 (HAI-1)
Acidic and hypoxic conditions of tumor microenvironment can activate matriptase (actM)
An imbalance in matriptase/HAI-1 ratio is observed in high-grade ovarian and prostate cancers
In mice, inhibition of actM by HAI-1 overexpression inhibits tumor progression
Overexpression of matriptase is evident in wide range of human epithelial tumors and B-cell lymphomas
Breast, lung, prostate, gastric, ovarian, colorectal, uterine, mantle cell lymphoma and others
High expression correlates with high malignancy grade and poor overall prognosis
First-in-class ADC targeting cell-surface protease may be ideal tumor eradication strategy
M69 mAb precisely targets actM followed by internalization and selective killing of tumor cells
ActM expression almost exclusively on tumor cells, not surrounding stromal cells, at every stage of carcinogenesis
Potential to inhibit multiple tumor pathways that perpetuate tumor progression
Sources:
Benaud Eur J Biochem 2001; Oberst Am J Path 2001; Oberst Clin Cancer Res 2002
Saleem Cancer Epidemiol Biomarkers Prev 2006; List Genes Dev 2005
Illustration: Lee AJP Cell Physio 2007
Note: M69 mAb binds only activated and not latent matriptase
ActM Enhancement of Multiple Pro-tumor Pathways
ActM engages multiple substrates that can drive tumor invasiveness and metastasis when activated
Protease activity promotes extracellular matrix degradation
Activation of urokinase-type plasminogen activator (uPA)
Degradation of fibronectin and laminin
Hepatocyte growth factor (HGF) activates signaling pathways that stimulate proliferation and invasiveness through c-Met receptor
Protease-activated receptor (PAR-2) activation enhances cell proliferation and migration
Illustrations: Lee J Cancer Molecules 2006