TMOD-33. ESTABLISHMENT AND PRELIMINARY EVALUATION OF BEVACIZUMAB-RESISTANT GLIOMA XENOGRAFT MODELS

Abstract High-grade gliomas characteristically exhibit aberrant neovascularization which is thought to play an important role in GBM progression. One of the main drivers of angiogenesis in GBM is vascular endothelial growth factor A (VEGF-A), which binds to VEGF receptors on endothelial cells and stimulates neovascularization and vascular permeability. For these reasons, VEGF-A mediated signaling is an attractive target for developing anti-angiogenic therapies for GBM. Clinical trials in GBM patients have shown that treatment with bevacizumab, a humanized anti-VEGF-A antibody, is associated with improvements in radiographic response, progression-free survival and quality of life. Despite these benefits, patients inevitably develop resistance and frequently fail to demonstrate significantly better overall survival. A critical issue in GBM research is to develop a better understanding of mechanisms of resistance to VEGF-targeted therapies and their clinical importance in GBM relapse. To address this question, we established two patient derived xenograft (PDX) lines from which bevacizumab-resistant sub-lines were generated by prolonged treatment over serial passages. Parental lines were generated from tumor tissue acquired at the time of tumor resection originating from newly diagnosed, untreated patients and subcutaneously engrafted in athymic mice. Tumors from initial subcutaneous parental PDXs were then serially treated with bevacizumab (5mg/kg, IP twice weekly, 5 weeks) and passed until resistance was obtained. Sensitivity to bevacizumab was reduced by 54–87% and 52–90% in subcutaneous and intracranial models respectively. Treatment with a panel of standard of care therapies are currently underway to identify differences in response rates between parental and bevacizumab-resistant PDX models. Furthermore, studies are ongoing to characterize differences in mutational profiles, gene expression signatures, and cytokine production between bevacizumab sensitive and resistant PDX lines. Results from these studies will be used to investigate novel therapeutic combinations aimed at overcoming resistance to chemotherapies and anti-angiogenic agents in GBM.