Purpose: Pancreatic neuroendocrine tumors (PNETs) represent a rare but challenging heterogeneous group of cancers with an increasing incidence over the last number of decades. Herein, we report an in depth evaluation of the new anti-angiogenic small-molecule tyrosine kinase inhibitor (TKI) nintedanib in the preclinical Rip1Tag2 transgenic mouse model of neuroendocrine carcinoma of the pancreas (insulinoma). Experimental design: We have assessed the anti-angiogenic and anti-tumor activity of nintedanib, in comparison to other anti-angiogenic TKI, by treating Rip1Tag2 transgenic mice with different treatment schedules complemented with histopathological, cell biological and biochemical analyses. Results: Prolonged nintedanib treatment of Rip1Tag2 mice has led to a strong suppression of angiogenesis, accompanied by a reduced tumor burden, which translated into a significant prolongation of survival. Despite nintedanib's inhibitory action on perivascular cells, the blood vessels remaining after therapy displayed a considerably mature phenotype with tight perivascular cell coverage and preserved perfusion. Nintedanib treatment did not increase local tumor invasiveness or metastasis to the liver and pancreatic lymph nodes - a phenomenon which has been observed with anti-angiogenic treatments of Rip1Tag2 transgenic mice in other laboratories. In contrast to the strong reduction in blood microvessel densities, nintedanib did not have any impact on tumor lymphangiogenesis. Conclusions: Based on our findings we propose the clinical evaluation of the anti-angiogenic drug nintedanib as a new treatment modality of PNET patients, notably in a direct comparison to already established therapeutic regimen such as sunitinib.
- Received December 23, 2014.
- Revision received July 7, 2015.
- Accepted July 14, 2015.
- Copyright © 2015, American Association for Cancer Research.