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Ai-24 Vegfr Inhibitors Enhance Progression Of Neuro-Oncology 16:v1–v7, 2014. doi:10.1093/neuonc/nou238.24 anti-VEGF targeted therapy is inevitable and in many instancesthe disease pre- NEURO-ONCOLOGY sents with a more aggressive phenotype. Recently completed phase III trials evaluating BVZ in combination with chemoradiation in newly diagnosed GBM also failed to establish an overall survival benefit. Hence there is a critical need to understand why anti-angiogenic therapies are ineffective in GBM pa- tients. In particular, knowledge of the mechanisms responsible for adaptive re- Abstracts sistance to VEGF/VEGFR targeting agents, that characterize recurring tumors, will be needed if significant advancement in prolonging survival rates of GBM patients is to be achieved. The results reported herein, suggest a potential mechanism by which anti-VEGF/VEGFR therapies regulate the enhanced invasive phenotype through a pathway that involves transforming growth factor beta (TGFb) receptor (TGFbR) and chemokine receptor AI-24. VEGFR INHIBITORS ENHANCE PROGRESSION OF CXCR4. The VEGFR signaling inhibitors (Cediranib and Vandetanib) elevat- GLIOBLASTOMA BY UPREGULATING CXCR4 IN A TGFbR ed the expression of CXCR4 in VEGFR-expressing primary patient-derived SIGNALING-DEPENDENT MANNER GBM cell lines and tumors, and enhanced the in vitro migration of these Downloaded from https://academic.oup.com/neuro-oncology/article/16/suppl_5/v6/1052919 by guest on 29 September 2021 Kien Pham1, Defang Luo1, Dietmar Siemann1, Brian Law1, Brent Reynolds1, lines toward CXCL12. The combination of Cediranib and the CXCR4 antag- Parvinder Hothi2, Gregory Foltz2, and Jeffrey Harrison1; 1Departments of onist AMD3100/Plerixafor provided a greater survival benefit to tumor- Pharmacology & Therapeutics, Radiation Oncology, and Neurosurgery, bearing animals, compared to monotherapies with these agents. The upregu- Preston A. Wells Jr. Center for Brain Tumor Therapy, University of Florida, lation of CXCR4 by VEGFR inhibitors was dependent on TGFb/TGFbR, Gainesville FL, USA; 2The Ben and Catherine Ivy Center for Advanced Brain but not HGF/MET, signaling activity, suggesting a mechanism of crosstalk Tumor Treatment, Swedish Neuroscience Institute, Seattle, WA, USA among VEGF/VEGFR, CXCL12/CXCR4, and TGFb/TGFbR pathways in the malignant phenotype of recurrent tumors after anti-VEGF/VEGFR thera- The failure of standard of care treatment for patients diagnosed with glio- pies. Thus, the combination of VEGFR, CXCR4, and TGFbR inhibitors could blastoma (GBM) coupled with the highly vascularized nature of this solid provide an alternative strategy to halt GBM progression. tumor has led to the consideration of agents that target vascular endothelial growth factor (VEGF) or its receptors, as alternative therapeutic strategies for this disease. While early clinical studies determined that recurrent GBMs respond favorably to bevacizumab (BVZ), progression of tumors after Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2014..
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