Abstract 4218: Diffusion-weighted MRI can predict response to aflibercept in in vivo models
Authors: Fleten Karianne G. , Bakke Kine M. , Abildgaard Andreas , Mælandsmo Gunhild M. , Redalen Katrine Røe , Flatmark Kjersti 
Published: July 2016

Abstract
BACKGROUND: The liver is the most frequent metastatic site in colorectal cancer (CRC), and relevant in vivo models are needed to study the efficacy of anticancer drugs in this setting. Aflibercept, targeting vascular endothelial growth factors A and B and placental growth factor, is one of the most recently approved antiangiogenic agents for treatment of metastatic CRC. In the present work, the efficacy of aflibercept was investigated in experimental models of liver metastases in nude mice and growth progression was monitored using non-invasive imaging.
METHODS: Liver metastases were established in mice by intrasplenic injection of CRC cell lines HCT116 and HT29 transfected with luciferase. Magnetic resonance imaging (MRI) (7T) and bioluminescent imaging (IVIS spectrum) were used to monitor tumor growth. Aflibercept was delivered intraperitoneally. To further characterize treatment response in metastatic tumors, diffusion-weighted (DW)-MR images were obtained. At termination tumors were sampled for histopathologic analysis.
RESULTS: Mice bearing HCT116 xenografts responded well to treatment and a significant increase in survival compared to vehicle treated animals was observed (p&lt; 0.001), in addition to decreased tumor burden. No increase in survival was observed upon aflibercept treatment in HT29 xenografts (p = 0.155), whereas in one of two experiments performed a significant reduction in tumor volume was observed, suggesting that there was a slight response to treatment.
T2-weighted MRI was used to quantify tumor volume by manual delineation using the OsiriX software. MRI-assessed tumor volumes correlated well with tumor weight at the time of termination, while for bioluminescence measurements no such correlation was observed. In contrast, bioluminescence was a sensitive detection method early in the experiments when MRI did not show liver tumor.
DW-MRI was obtained and apparent diffusion coefficient (ADC) tumor maps were calculated using the nordicIce software. A slight increase in ADC values was observed for HT29 tumors while there was a large increase in ADC values for HCT116 tumors after treatment with aflibercept. This corresponded well with histologic evaluation of tumors, showing increased necrosis in HCT116 tumors, but not in HT29 tumors.
CONCLUSION: Our results demonstrate efficacy of aflibercept in an orthotopic model of liver metastases in CRC. MRI could be used to monitor treatment efficacy with high precision, while bioluminescence measurement could detect small-volume disease with high sensitivity, but was less specific in high-volume disease. Interestingly, ADC values obtained from DW-MRI were highly predictive of treatment response by clearly visualizing and quantifying tumor necrosis.
Citation Format: Karianne G. Fleten, Kine M. Bakke, Andreas Abildgaard, Gunhild M. Mælandsmo, Katrine Røe Redalen, Kjersti Flatmark. Diffusion-weighted MRI can predict response to aflibercept in in vivo models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4218.