TMOD-02: BLOCKING CXCR4 INCREASES SURVIVAL IN A MOUSE MODEL OF NEURAL STEM CELLS-DERIVED GLIOBLASTOMA BY BLOCKING AN AUTOCRINE POSITIVE FEEDBACK LOOP REGULATING APOPTOSIS AND CELL CYCLE PROGRESSION VIA Rb1 AND cdk4/cdk6/CyclinD1

The current standard of care for glioblastoma (GBM), the most common form of glioma, can provide a median-survival of only 15 months. Treatment failure is thought to be due to the heterogeneous nature of the disease and the persistence of glioma-stem-cells. In a screen for chemokines secreted by GBM cell lines we identified CXCL12 with highest expression in glioma cells derived from the malignant transformation of neural stem cells. In human GBM, expression of CXCL12 and of its cognate receptor CXCR4 correlates with increase in tumor grade. In our mouse model, tumors were induced with oncogenic DNA (NRAS and SV40-LgT) injected into the lateral ventricles of neonatal mice. Transformed cells proliferate towards the brain parenchyma or travel alongside CXCL12 + vascular endothelial cells to form supra-tentorial tumors in the cortex, striatum or hippocampus. These tumors express the stem cell markers Nestin and Olig2 and render animals moribund within 30 days. Mature tumors harbor the histological hallmarks of human GBM. Treatment with Plerixafor, a CXCR4 inhibitor, extends the median-survival to 53 days (p = 0.0006). Cell lines derived from these tumors treated with Plerixafor show an increase in apoptosis after 72h, which correlates with a decrease in Rb1. After 96h expression of CXCL12 increases 6-fold. This increase is blocked by Plerixafor, accompanied by a decrease in cell cycle progression, expression of cdk4/cdk6 and cyclin D1. Administration of CXCL12 rescues the decrease in proliferation induced by Plerixafor. This data show that in neural stem cell derived GBMs the CXCL12/CXCR4 axis operates via an autocrine positive feedback mechanism promoting survival and cell cycle progression. The retinoblastoma pathway is altered in 75% of primary human GBM making cdk4/cdk6 pharmacological inhibitors ineffective in arresting cell cycle progression. We propose that blocking CXCR4 may represent a therapeutic strategy to prevent the growth of Rb1 deficient GBM.