PO-315 Intertumor heterogeneity in vascularity and response to bevacizumab treatment in artificial melanoma brain metastases

Introduction Patients diagnosed with melanoma brain metastases have few treatment options and poor prognosis, and antiangiogenic agents targeting the vascular endothelial growth factor A (VEGF-A) could represent a potential treatment strategy. The purpose of this preclinical investigation was to study the vascularisation pattern and the effect of the VEGF-A targeting agent bevacizumab in artificial brain metastases established from four human melanoma cell lines with different angiogenic and invasive properties. Material and methods A-07, D-12, R-18, and U-25 cells transfected with GFP were injected intracerebrally in nude mice treated with bevacizumab (10 mg/ml) or vehicle. Treatment was initiated one day before tumour cell injection, and continued twice a week until the mice became moribund. Moribund mice were killed and autopsied, and the brain was evaluated by fluorescence imaging or by histological examination. Expression and secretion of factors involved in angiogenesis and invasion was assessed by quantitative PCR and ELISA. Results and discussions The melanoma cells showed a preference for growth in the meninges and ventricles after intracerebral injection, and intertumor heterogeneity in the aggressiveness of meningeal tumours reflected differences in angiogenic activity and expression of VEGF-A and interleukin 8 (IL-8). In contrast, growth and invasion of the brain parenchyma relied primarily on vascular co-option. The response to bevacizumab treatment depended on the angiogenic signature of the tumour cells and on the intracranial growth site. Bevacizumab treatment resulted in delayed meningeal tumour growth and prolonged survival in cell lines showing high VEGF-A expression and high angiogenic activity in the meninges, whereas no difference in survival was observed between bevacizumab-treated and vehicle-treated mice in cell lines showing low VEGF-A expression and lower angiogenic activity in the meninges. Conclusion The melanoma cell lines showed different response to bevacizumab treatment, and these differences reflected differences in intracranial vascularisation patterns and in expression of VEGF-A.