PNNL

Abstract

Despite wide use of anti-vascular endothelial growth factor (VEGF) therapy for many solid 30 cancers, most of them become resistant to this therapy and develop into progressive disease. 31 Therefore, new biomarkers and strategies for blocking adaptive resistance of cancer to anti-VEGF therapy are needed. As described herein, we found that cancer-derived small extracellular vesicles (EVs) package increasing quantities of VEGF and other factors in response to anti-VEGF therapy. Notably, small EV-VEGF (eVEGF) is not recognized by bevacizumab and can be transferred to endothelial cells and trigger intracrine signaling and promote angiogenesis. Also, serum eVEGF was present at higher levels in ovarian cancer mouse models with adaptive resistance to bevacizumab than in models sensitive to it. Ovarian cancer cell-derived eVEGF increased tumor growth despite treatment with bevacizumab. Notably, the eVEGF level was elevated in patient serum after bevacizumab-containing therapy. Proteomic data of small EVs from mouse models suggested that several novel biomarkers are promising for drug response prediction. Collectively, these data demonstrated a new mechanism whereby eVEGF evades recognition by therapeutic antibodies and promotes tumor angiogenesis and progression. These findings have clinical implications for biomarkers and new therapeutic strategies for ovarian cancer.