207 Intetumumab, an Anti-pan αvβ Integrin Antibody, Reduces Tumor Burden in an Experimental Model of Established Lung Metastasis

Abstract

cells into the left adrenal gland were treated with the specific VEGFR-1−3 tyrosine kinase inhibitor at 30 mg/kg/day during 28 days. Tumor growth was followed by ultrasound and bioluminescence; tumors and organs were harvested 24 hours after end of treatment to evaluate the presence of tumor cells. Comparative genomic analysis was performed on treated versus control tumors, metastases versus their respective primary tumors. Results: Significant tumor inhibition was detected at Day 25 (p = 0.0255) with a heterogeneous distribution of tumor volumes (median = 18 mm 3 , range 3−136) in treated mice as compared to controls (median= 55 mm 3 , range 9−330), associated with a decrease of vasculature density. While VEGFR1 and AKT remain activated in control and non responding tumors, both pathways were found inhibited in tumors that were responding to the specific VEGFR-1−3 tyrosine kinase inhibitor whereas SRC was activated. At autopsy, the pan-VEGFR inhibitor treated mice presented more frequently with macrometastases in liver and spleen as compared to controls. Metastases were confirmed by bioluminescence imaging. Through histology analyses, we detected metastases independent of primary tumor size and presence of infiltrating micrometastases. Gene expression analysis is currently ongoing. Conclusion: Inhibition of VEGFR pathways with the pan-VEGFR inhibitor exhibited moderate antitumor activity in the orthotopic IGR-N91 neurob- lastoma model associated with inhibition of neovascularization. Enhanced detection of macrometastases and infiltrating micrometastases suggest activation of different signaling pathways associated with proliferation or migration involved in the escape mechanism to antiangiogenic treatment.