Abstract 4271: Combination of VEGF Trap (Aflibercept) with docetaxel, but not with gemcitabine, is efficacious in tumors resistant to anti-VEGF therapy

Abstract

Abstract Increased anti-tumor efficacy is often observed when VEGF blockade is combined with certain chemotherapy agents. However, the mechanism by which combination treatment with certain agents, but not others, results in enhanced anti-tumor effects is poorly understood. In this study, we compared the anti-tumor effects of VEGF Trap in combination with either docetaxel or gemcitabine on HT1080, a human fibrosarcoma tumor line that is resistant to anti-VEGF treatment. Immunodeficient SCID mice bearing subcutaneous HT1080 tumors (size ∼150 mm3) were treated with either control protein plus vehicle, VEGF Trap, chemotherapy agent (docetaxel or gemcitabine), or the combination. Following three treatments administered every 3-4 days, tumors were harvested either one day after the final dose or allowed to grow and harvested when the average size of the treatment group reached ∼500mm3. We found that combination treatment with VEGF Trap plus docetaxel was significantly more effective compared to single agents, while there was no added benefit of combining VEGF Trap with gemcitabine. Although treatment with chemotherapy agents alone and in combination with VEGF Trap both initially regressed tumor size, only the combination with docetaxel was effective at delaying long-term tumor re-growth. Immunohistochemical analysis of tumors showed that both combination regimens produced a dramatic decrease in the number of proliferating tumor cells. However, only VEGF Trap and docetaxel combination treatment resulted in pruned tumor vessels with less branching, whereas VEGF Trap plus gemcitabine had minimal effect on tumor vessel morphology. Furthermore, VEGF trap plus docetaxel produced an increase in TUNEL-positive cells associated with the tumor vasculature and a marked decrease in tumor pericytes. These results suggest that in tumors resistant to VEGF blockade, taxanes (docetaxel) can sensitize the vasculature to anti-VEGF treatment (aflibercept), thus resulting in enhanced effects on the tumor vessels and improved anti-tumor efficacy. Further understanding of the mechanistic basis of different combination regimens may allow improvement of current strategies to treat tumors resistant to antiangiogenic therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4271. doi:10.1158/1538-7445.AM2011-4271