Abstract B09: Nintedanib inhibits tumor and vessel growth and leads to vascular normalization in A549-NSCLC-xenografts

Abstract

Abstract Angiogenesis plays a major role in the growth and progression of non-small-cell lung cancer (NSCLC). The triple angiokinase inhibitor nintedanib is a potent inhibitor of the receptor tyrosine kinases FGFR-1, 2, 3, PDGFR-α and β, VEGFR-1, 2, 3. and Flt-3. as well as of non-receptor tyrosine kinases like Src, Lyn and Lck by occupying the intracellular ATP-binding pocket. In the pivotal LUME-Lung 1 trial Nintedanib plus docetaxel has proven an overall survival benefit over docetaxel monotherapy in second-line treatment of non-small-cell lung cancer of adenocarcinoma. The aim of this study was to analyse treatment induced vascular normalization of nintedanib, bevacizumab and docetaxel alone versus the respective combinations with docetaxel. Athymic NCRNU-M-F nude mice with subcutaneous A549-NSCLC xenografts were treated with nintedanib (50mg/kg), bevacizumab (10mg/kg) and docetaxel (10mg/kg) alone versus the combination of nintedanib (50mg/kg) + docetaxel (10mg/kg) or bevacizumab (10mg/kg) + docetaxel (10mg/kg)Treatment started seven days after tumor cell inoculation, when the mean tumor volume was ∼200 mm3, and lasted two weeks. The tumor sizes were measured three times a week with calipers. Vessel densities (anti-CD31), cellular proliferation (anti-Ki67) and lymphangiogenesis (anti-LYVE1) were assessed morphometrically by immunohistochemistry. Microvascular corrosion casting was used to analyze and evaluate two- and three-dimensionally the morphology and architecture of blood vessels. Tumor volumes were significantly reduced under nintedanib treatment whereas docetaxel resulted in non-significant tumor growth differences as compared to the controls. The bevacizumab-treated groups were just in-between. This was also true for the vessel densities: significant lower vascular densities were seen only in the nintedanib and combi treatment groups. Docetaxel alone had no significant impact on vessel densities. Microvascular corrosion casting and 3D-morphometry showed significantly qualitative and quantitative differences in the treatment groups. The intervascular distances and interbranching distances were significantly altered towards more control values, evident also in the microscopic appearance of a normalized microvascular architecture. Docetaxel alone had also an effect on these parameters, however, to a far lesser extent. The same is true for the vessel diameters. The absolute vascular volume was significantly lower in the nintedanib and combi treatment groups whereas the relative percentual vascular volume did not show significant differences. Quantitative analyses of anti-ki67 stained sections showed significantly less proliferation in the nintendanib single and combi treatment groups. In summary, we conclude a significant positive therapeutic effect of nintedanib on the microvascular architecture and tumor growth inhibition in A549-NSCLC-xenografts. The vascular architecture in nintedanib treated tumors was characterized by a strong normalization of vasculature. This emerging concept of vascular normalization might be mainly attributable for the significant anti-tumorigenic effects of combinatorial treatment with nintedanib and docetaxel in the NSCLC-xenografts. Citation Format: Maximilian Ackermann, Frank Hilberg, Moritz Anton Konerding. Nintedanib inhibits tumor and vessel growth and leads to vascular normalization in A549-NSCLC-xenografts. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr B09.