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RESEARCH PRODUCT

P08.76 Anti-EGFL7 treatment as an add-on for glioma therapy

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Glioblastoma multiforme (GBM) is one the most common and malignant forms of brain tumors. The median survival time of patients diagnosed with primary GBM is around 15 months. In spite of multimodal treatments GBMs remain essentially incurable. Therefore, alternative treatments targeting previously unexplored aspects of GBMs are required. However, the molecular mechanisms underlying the formation of brain tumors have only partially been defined. Especially Notch, a conserved developmental pathway, is promising in terms of GBM formation, as components of this signaling cascade are aberrantly expressed in gliomas. Studies reported that the inhibition of Notch decreased glioma cell proliferation in vitro and tumorigenicity in vivo. Previously, we identified the secreted protein EGFL7 as a novel Notch ligand, which promoted blood vessel formation. Therefore, we hypothesized that EGFL7 might affect glioma formation by the remodeling of the tumor vasculature. The tumor grade-dependent expression of EGFL7 in glioma specimens has been shown by an AffyU133Plus2 gene expression array and by quantitative RT-PCR. Immunohistochemical stainings of glioma specimens displayed vessel-specific expression of EGFL7. Intracranial xenograft implantations of U87 glioma cells, ectopically expressing EGFL7, caused a decreased survival rate of nude mice. This oncogenic potential of EGFL7 was further validated by alternative mouse models, e.g., by the intracranial implantation of murine GL261 glioma cells in immunocompetent mice or in EGFL7 knock-out animals. GBMs are characterized by abnormal, highly permeable blood vessels and low oxygen tension. Quantitative immunohistochemical analysis revealed more mature blood vessels in EGFL7-treated experimental tumor specimens. Consequently, these vessels were less leaky as detected by MRI analyses subsequent to Gadovist injection. On the molecular level, EGFL7 affected the cell surface levels of integrin α5β1, a receptor of the extracellular matrix protein fibronectin, thereby altering cell adhesion. Experimental glioma bearing mice treated with an anti-EGFL7 blocking antibody displayed an increased average survival time as compared to animals treated with isotype control. This prolonged survival was comparable to VEGF inhibition and both agents acted synergistically during treatment. Thus, inhibiting EGFL7 along with VEGF improves survival in experimental glioma models and might add to the current therapies of GBM patients.