Abstract A03: Vascular function affected fundamentally different by different antiangiogenic agents

Abstract

Abstract The purpose of this preclinical study was to investigate the effect of two antiangiogenic agents, properdistatin and sunitinib, on the morphology and function of tumor vasculature. Properdistatin is a novel peptide derived from the thrombospondin-1 domain of the plasma protein properdin. Properdistatin treatment has been shown to inhibit angiogenesis and tumor growth in breast cancer xenografts. Sunitinib is a tyrosine kinase inhibitor that interacts with several receptors including vascular endothelial growth factor receptors 1-3, and platelet-derived growth factor receptors α-β. Sunitinib treatment has been shown to inhibit angiogenesis and tumor growth in a number of tumor models, and has been approved clinically for several indications. A-07 human melanoma xenografts grown in dorsal window chambers or as intradermal flank tumors were used as preclinical tumor model. In window chamber tumors, morphologic parameters of tumor vascular networks were assessed from high-resolution transillumination images, and blood supply time and plasma velocities were assessed from first-pass imaging movies recorded after a bolus of 155kDa tetramethylrhodamine isothiocyanate-labeled dextran had been administered intravenously. In flank tumors, parametric images of ADC and Ktrans were produced from diffusion weighted magnetic resonance imaging (DW-MRI) and dynamic contrast-enhanced MRI (DCE-MRI). Tumor hypoxia and necrosis were assessed from immunohistochemical preparations of the imaged tissue, and tumor interstitial fluid pressure (IFP) was assessed with probe measurement. Properdistatin treatment reduced the density of small-diameter vessels, reduced blood supply time, and increased plasma velocities, whereas sunitinib treatment did not alter blood supply time, reduced overall vessel density, induced tumor hypoxia and necrosis, and did not alter tumor IFP. Sunitinib-treated flank tumors showed reduced Ktrans values corresponding to a decrease in vessel density, and increased ADC values corresponding to induction of tumor necrosis. In conclusion, properdistatin treatment improved vascular function, whereas sunitinib treatment did not improve vascular function but induced tumor hypoxia and necrosis in A-07 tumors. This data demonstrates that different antiangiogenic agents may affect vascular function fundamentally different in the same tumor model. DW-MRI and DCE-MRI were sensitive to the sunitinib-induced changes in the tumor microenvironment, demonstrating that these MR-techniques may be used to identify tumors where antiangiogenic treatment does not improve vascular function. Citation Format: Jon-Vidar Gaustad, Trude G. Simonsen, Tord Hompland, Lise Mari K. Andersen, Einar K. Rofstad. Vascular function affected fundamentally different by different antiangiogenic agents. [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 A03.