Abstract 1799: The effect of dovitinib on angiogenesis in human neuroendocrine tumors

Background: Dovitinib is a potent oral inhibitor of multiple angiogenic factors, including receptor tyrosine kinases (RTKs) such as VEGFR1-3, PDGFRβ, and FGFR1-3. Human neuroendocrine tumors (NETs) rely on these RTKs to mediate tumor development, metastasis and neovascularization. They usually originate in the small bowel and metastasize to lymph nodes (LNs) and/or liver (LV). Although antiangiogenic approach is a valid therapeutic option for metastatic NETs, currently there are no clinical trials on Dovitinib in human midgut NETs. We hypothesized that Dovitinib will inhibit angiogenesis in both primary (1°) and metastatic human NETs. Methods: Tissue samples from 126 NET patients were assayed in our in-vitro Human Tumor Angiogenesis model. Neovessels were visually scored and evaluated based on three parameters: percent initiation (%I), angiogenic growth (AG), and overall angiogenic response (OAR). Treatment doses [165 nM, n = 126; 82.5 nM, n = 94], tested on both 1° and metastatic NETs (LN, LV), were selected based on unpublished physiologic angiogenesis model data. Four normal and tissue-matched LV samples were tested at both doses. Angiogenesis data was analyzed for significance using Z-test (Primer) and paired t-test (MedCalc). Concentration of angiogenic factors in supernatant was measured by Human Angiogenesis/Growth panel (Milliplex, EMD Millipore). FGFR3 gene and protein levels were determined by TaqMan assay and immunohistochemistry staining on tissue-matched NETs. Results: Both Dovitinib doses achieved over 60% inhibition of%I in 1°, LV and LN tumors. Angiogenic growth was significantly (p