PATH-24. CXCR4 IS A POTENTIAL THERAPEUTIC TARGET FOR GLIOBLASTOMA AND DIFFUSE INTRINSIC PONTINE GLIOMAS

Abstract

Abstract Glioblastoma (GBM) is the most common adult malignant brain tumor with poor prognosis and Diffuse Intrinsic Pontine Glioma (DIPG) is a pediatric type of glioblastoma for which there is no effective therapy. CXCR4, a G-protein coupled receptor, has been shown to play a role in GBM invasion, cell survival, proliferation and angiogenesis. A CXCR4 inhibitor (AMD3100/Plerixafor) has been suggested as a potential therapeutic strategy for GBM with an isolated case report of a long-term survivor and an ongoing clinical trial evaluating its effects in GBM patients. However, there is a poor understanding of the expression of CXCR4 in GBM and DIPGs. In this study, we evaluated the expression of CXCR4 in 21-DIPG and 36-GBM cases. In GBMs, CXCR4 was expressed in 5.6% of cases in tumor cells and in 19.4% of cases in endothelial cells in blood vessels. In DIPGs, we observed expression of CXCR4 in 28.6% of cases in tumor cells and in 14.3% of cases in endothelial cells. We observed absence of CXCR4 expression in all IDH-mutant GBMs. There was no correlation between CXCR4 or EGFR expression, p53-mutations or H3F3A p.K27M mutations in DIPGs. There was a trend of poorer prognosis in CXCR4 positive DIPGs but the difference did not reach statistical significance. Furthermore, we evaluated the effects of Plerixafor in the survival of DIPG and U87-GBM cell lines and observed a dose-dependent reduction in cell viability. RT-PCR and immunohistochemistry of DIPG cells showed variable CXCR4 expression in the cell lines that did not correlate with sensitivity to Plerixafor. In conclusion, in vitro experiments show that the CXCR4 inhibitor Plerixafor is a potential therapeutic strategy for GBM and DIPGs. However, CXCR4 is not universally expressed in glioblastomas and its expression should be considered in clinical trials that evaluate the efficacy of CXCR4 inhibitors in GBM and DIPGs.