SC-03PAR1 INHIBITION SUPPRESSES A2B5-DEFINED GLIOMA PROGENITOR CELLS AND THEIR DERIVED GLIOMAS IN VIVO

In a comparison of gene expression by A2B5-defined glial tumor progenitor cells (TPCs) to glial progenitor cells derived from normal adult human brain (Cell Reports 3:2127-41, 2013), we found that the F2R gene encoding PAR1 was differentially over-expressed by TPCs isolated from primary gliomas at every stage of glioma progression. In this study, we therefore asked if PAR1 activation was causally associated with glioma progression. Lentiviral shRNAi knock-down of PAR1 inhibited the expansion and proliferation of glioma TPCs in vitro. We further found that the PAR-1 receptor antagonists SCH79797 and SCH530348 (vorapaxar) inhibited A2B5+ TPC expansion and migration in vitro. PAR1 knockdown also suppressed the tumorigenic potential of A2B5+ TPCs after transplantation into the brains of immunodeficient mice. In addition, mice given subcutaneous grafts of A2B5+ human glioma TPCs exhibited delayed tumor growth if treated with Vorapaxar, relative to xenografted control mice treated with only vehicle. Together, these data suggest that PAR1 may contribute to glioma progenitor expansion and tumor growth; as such, the abrogation of PAR1 signaling may contribute to the treatment of malignant glioma.