Abstract B14: The effect of sunitinib treatment in human melanoma xenografts: Associations with angiogenic profiles

Abstract

Abstract The effect of antiangiogenic agents targeting the vascular endothelial growth factor A (VEGF-A) pathway has been reported to vary substantially in preclinical studies. Treatments with these agents have induced substantial reductions in vessel density in some tumor models, and minor or no reductions in vessel density in others. Additionally, the treatments have improved vascular function and oxygenation in some tumor models, and induced hypoxia in others. The purpose of this study was to investigate the effect of sunitinib treatment on the morphology and function of tumor vasculature in melanoma xenografts with different angiogenic profiles. A-07, U-25, D-12, and R-18 melanoma xenografts grown in dorsal window chambers were used as preclinical tumor models. Tumor-bearing mice were treated with sunitinib (40 mg/kg/day) or vehicle. Morphologic parameters of tumor vascular networks were assessed from high-resolution transillumination images, and tumor blood supply times were assessed from first-pass imaging movies recorded after a bolus of 155 kD tetramethylrhodamine isothiocyanate-labeled dextran was injected intravenously. Tumor hypoxia was assessed in immunohistochemical preparations by using pimonidazole as hypoxia marker, and the gene expression and the protein secretion rate of angiogenic factors were assessed by quantitative PCR and ELISA, respectively. The melanoma lines differed substantially in the expression of VEGF-A, VEGF-C, and platelet-derived growth factor A. Sunitinib treatment reduced vessel densities and induced hypoxia in all melanoma lines, and the magnitude of the effect was associated with the gene expression and protein secretion rate of VEGF-A. Sunitinib treatment also increased vessel segment lengths, reduced the number of small-diameter vessels, and inhibited growth-induced increases in the diameter of surviving vessels, but did not affect blood supply times. In conclusion, sunitinib treatment did not improve vascular function but reduced vessel density and induced hypoxia in human melanoma xenografts. The magnitude of the treatment-induced effect was associated with the angiogenic profiles of the melanoma lines. Citation Format: Jon-Vidar Gaustad, Trude G. Simonsen, Lise Mari K. Andersen, Einar K. Rofstad. The effect of sunitinib treatment in human melanoma xenografts: Associations with angiogenic profiles. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B14.