Effect of regorafenib on angiogenesis in neuroendocrine tumors in vitro

• Published in: Journal of clinical oncology Vol. 34; no. 4_suppl; p. 232
• Main Authors: Milosavljevic, Tanja, Juge, Elise, Reeks, Adrianne, Owens, Jennifer, Wang, Yi-Zarn, Boudreaux, J Philip, Woltering, Eugene
• Format: Journal Article
• Language: English
• Published: 01.02.2016
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/jco.2016.34.4_suppl.232

Abstract only 232 Background: Regorafenib, a potent multikinase inhibitor, targets a broad range of receptor tyrosine kinases (RTKs), including but not limited to VEGFR, PDGFR, and FGFR, which play an integral role in angiogenesis. Human neuroendocrine tumors (NETs) rely on RTKs to mediate tumor neovascularization, development, and metastasis. Similar kinase inhibitors like PTK787 profoundly inhibit angiogenesis in human NETs. We hypothesized that Regorafenib would have antiangiogenic and antitumor effect on human NETs. This study demonstrates inhibitory activity of Regorafenib on pathologic angiogenesis in vitro using our human tumor angiogenesis model (HTAM). Methods: Human NETs were collected in cell culture media in the O.R. and transported to the laboratory at 4⁰C. Tumors were minced into 2 mm fragments, embedded in a fibrin-thrombin clot and supplemented with a nutrient culture media. Neovessels were visually scored and evaluated based on three parameters: percent initiation, angiogenic growth, and overall angiogenic response. An effective concentration was selected for all successive HTAM assays based on dose response experiments. Angiogenesis data was obtained for 77 patients and analyzed for significance using paired samples t-test (MedCalc). Results: Dose-dependent inhibition of angiogenesis was observed for all NETs (n = 77): primary tumors (n = 11), lymph nodes (n = 28) and organ (n = 38) metastases. Selected dose of Regorafenib [1100 nM] achieved statistically significant inhibition of angiogenic growth (59%) and overall angiogenic response (44.5%) in all NETs (p < 0.0001). However, there was no significant inhibition of percent initiation for all NETs except in primary tumors (p = 0.0260). Conclusions: Regorafenib is an effective antiangiogenic agent for NETs in-vitro. Regorafenib targets angiogenic growth in all NETs and inhibits initiation of angiogenesis exclusively in NET primary tumors. This suggests preferential use of Regorafenib for NET patients who have not yet developed metastases. Alternatively, Regorafenib could be an effective adjuvant treatment for advanced stage patients.