Abstract 5427: Combination of aflibercept (VEGF trap) and docetaxel produces increased antitumor effects associated with enhanced changes to tumor vasculature

Abstract

Abstract VEGF blockade in combination with chemotherapy has shown increased anti-tumor efficacy in preclinical models and clinical studies. However, the mechanism by which combination treatments result in enhanced effects is not well understood. In this study, we sought to characterize the mechanism for improved effects of aflibercept plus docetaxel on HT1080, a human fibrosarcoma line that is resistant to anti-VEGF treatment. Immunodeficient SCID mice bearing subcutaneous HT1080 tumors (size ∼100 mm3) were treated with either control protein (hFc) plus docetaxel vehicle, aflibercept (25 mg/kg s.c.), docetaxel (4.5 mg/kg i.v.), or the combination. Following three treatments administered every 3-4 days, tumors were left to grow and harvested when the average size of the treatment group reached ∼600mm3. We found that combination treatment with aflibercept plus docetaxel was significantly more efficacious than either single agent. Although treatments with docetaxel alone and in combination with aflibercept both initially regressed tumor size, the combination was significantly more effective at delaying long-term tumor regrowth. In tumors harvested 24 hrs after the last treatment, combination treatment produced a dramatic decrease in the number of proliferating cells and a concomitant increase in pyknotic cells. Aflibercept or docetaxel alone had only modest effects on the vessels in this tumor, whereas the combination treatment resulted in pruned vessels with less branching, some vessels with punctate endothelial cell staining, and an increase in TUNEL-positive endothelial cells. These results suggest that combination of aflibercept plus taxols (docetaxel) causes enhanced effects on the tumor vessels, thus improving efficacy in tumors with vasculature that exhibit resistance to VEGF blockade. Further understanding the mechanistic basis underlying these combination treatments may provide insight into improving current strategies to manage tumors resistant to antiangiogenic therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5427.