Abstract 1799: The effect of dovitinib on angiogenesis in human neuroendocrine tumors
Authors: Milosavljevic Tanja , Juge Elise , Casey Peter , Hall Michael , Woltering Eugene 
Published: July 2016

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doses [165 nM, n = 126; 82.5 nM, n = 94], tested on both 1° and metastatic NETs (LN, LV), were selected based on unpublished physiologic angiogenesis model data.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&lt;0.0001) inhibited in 1° (86.78%, 82.5 nM; 84.74%, 165 nM), LV (97.09%, 82.5 nM; 89.48%, 165 nM), LN (95.27%, 82.5 nM; 89.48%, 165 nM), and all NETs (86.76%, 82.5 nM; 84.74, 165 nM). Overall angiogenic response was reduced by over 88% in all NETs (p&lt;0.0001). Greater than 65% inhibition of OAR was observed in LV tumor (p = 0.0141, 82.5 nM; p = 0.0198, 165 nM), and matching normal tissue; however, normal tissue response was not statistically significant. Concentrations of VEGF pathway mediators (VEGFA, PlGF, VEGFC) were higher in LV tumor versus normal and down-regulated in response to Dovitinib. Gene and protein FGFR3 levels were increased in all three NET sites compared to normal.

Conclusions: Our preclinical results demonstrate robust efficacy of Dovitinib in inhibiting angiogenesis in human midgut NETs in vitro. Dovitinib effectively inhibits angiogenesis in both primary and metastatic sites by more than 60% at both doses by simultaneously targeting VEGF pathway and FGFR3. Comparatively, dovitinib targets mechanisms of angiogenic growth more effectively than those involved in initiation. This study provides a compelling rationale for future clinical investigation of Dovitinib antiangiogenic therapy in patients with NETs.

Citation Format: Tanja Milosavljevic, Elise Juge, Peter Casey, Michael Hall, Eugene Woltering. The effect of dovitinib on angiogenesis in human neuroendocrine tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1799.