Abstract 2665: Dynamic contrast-enhanced ultrasound monitoring of tumor perfusion in a murine pancreatic tumor model to assess the effect of (ziv)-aflibercept and sorafenib, two anti-angiogenic drugs.
Authors: Lamuraglia Michele , Barrois Guillaume , Santin Mathieu , Le Guillou-Buffello Delphine , Bridal Lori S. , Lucidarme Olivier 
Published: August 2014

Abstract
Background: anti-angiogenic drug combinations provide a promising new therapeutic approach. Noninvasive monitoring techniques would help to choose drug based on patient response. The effects on tumor perfusion by combining Ziv-aflibercept (VEGF-Trap is being developed as a part of a collaboration between Sanofi and Regeneron Pharmaceuticals, Inc.) and Sorafenib (NexavarTM, Bayer Schering Pharma) was tested. Methods: pancreatic adenocarcinomas were induced by subcutaneous injection of 100 μl containing 1 x 106 MIA PaCa2 cells in the left flank of 50 female, 2-4 week-old, nude mice (Naval Medical Research Institute [NMRI] Elevage Janvier, Le Genest-St-Isle, France). Dynamic contrast-enhanced ultrasound (DCE-US) was performed using an Aplio 50 ultrasound imaging system with a 12-MHz probe (PLT 1202 S, TOSHIBA, Tokyo, Japan). DCE-US data sequences were acquired after intravenous injection of a 100 μl bolus of Luminity contrast agent. Data were acquired from each mouse on days 15, 16 and 24 after tumor cell injection. Treatment was started on day 15 just after DCE-US baseline scan. Fifty mice were included in this study: 15 controls received placebo, 11 mice were treated with sorafenib (60 mg/kg/day by gavage), 12 mice were treated with ziv-aflibercept (40 mg/kg2 twice a week by injection) and 12 mice were treated with the combination of the two anti-angiogenic drugs. Image sequences were recorded in raw data format and extracted with TOSHIBA software (CHIQ) allowing calculation of the linear time-intensity curve in regions of interest within the tumor. Using in-house software, the time-intensity bolus curve was fit to a lognormal model from which the Area Under the Curve (AUC) was calculated to assess microvascular perfusion in the tumor. Statistical analysis was performed using Wilcoxon Signed-Rank tests. Results: the AUC decreased significantly from day 15 to day 16 for the group receiving ziv-aflibercept (p=0,020) and for the group receiving the combination of ziv-aflibercept and sorafenib (p=0,005), while no significant differences were found for the placebo or sorafenib monotherapy groups. From day 15 to day 24, the AUC obtained from the fit to the bolus curve decreased significantly for the group receiving the combination of ziv-aflibercept and sorafenib (p=0,031), while no significant differences were found for the three other groups. Conclusions: the DCE-US functional evaluation used in this study demonstrated that the association of the combination of ziv-aflibercept and sorafenib and ziv-aflibercept alone reduced functional perfusion in the tumor 24 hours after therapy onset. The long term (9 days) perfusion reduction was maintained for combined therapy but was not significant for placebo, ziv-aflibercept or sorafenib mono-therapy.
Citation Format: Michele Lamuraglia, Guillaume Barrois, Mathieu Santin, Delphine Le Guillou-Buffello, Lori S. Bridal, Olivier Lucidarme. Dynamic contrast-enhanced ultrasound monitoring of tumor perfusion in a murine pancreatic tumor model to assess the effect of (ziv)-aflibercept and sorafenib, two anti-angiogenic drugs. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2665. doi:10.1158/1538-7445.AM2013-2665