Abstract 4246: Enhanced anti-vascular and anti-tumor effects upon combination therapy with aflibercept (VEGF Trap) and other anti-angiogenic drugs

Abstract

Abstract Experimental and clinical development of anti-angiogenic drugs to date has mostly focused on the VEGF pathway, although other signaling pathways, including Dll4-Notch and Angiopoietin-Tie, are now also being explored. Targeting one pathway, however, might not result in maximum anti-vascular and anti-tumor effects. In this study, we compared the rapid effects on tumor perfusion of single agent blockade of VEGF, Dll4 or Ang2 to the effects of combined therapy (VEGF blockade plus either Dll4 or Ang2 blockade), and compared long-term tumor growth responses to these early effects on tumor perfusion. Using aflibercept (VEGF Trap) alone and in combination with a blocking Dll4 antibody or a blocking Ang2 antibody, we compared various tumors with a wide range of long-term growth responses to each agent: C6 rat glioma tumors, HT1080 human fibrosarcoma and Colo205 human colon carcinoma tumors, all grown subcutaneously in SCID/CB17 mice. Tumor vascular perfusion was assessed using contrast-enhanced micro-ultrasound at 24 and 72 hr after treatment. We found that aflibercept treatment rapidly decreased vascular perfusion in C6 (59% after 24 hr) and Colo205 (32%) tumors, whereas there was no decrease observed in HT1080 tumors. These changes in perfusion correlated with long-term tumor growth inhibition upon aflibercept treatment. Dll4 blockade resulted in decreased vascular perfusion in C6 (30% after 24 hr), Colo205 (77%), and HT1080 (54%) tumors, which again correlated with long-term growth inhibition of the different tumors. Treatment with an anti-Ang2 antibody produced a slight decrease in perfusion of Colo205 tumors (13% after 24 hr), associated with a decrease in tumor growth. However, combination treatments with aflibercept plus either anti-Dll4 or anti-Ang2 antibodies were more potent in all tumor types compared to single agent treatments at reducing tumor perfusion as well as inhibiting long-term tumor growth. Taken together, these data show that changes in tumor perfusion correlate with long-term tumor responses to combination treatment of aflibercept plus either anti-Dll4 or anti-Ang2 antibody suggesting that decreases in tumor perfusion could be an early biomarker predictive of response to anti-angiogenic therapies. Measuring the increased effectiveness of combination therapy in patients treated with different anti-angiogenic drugs may facilitate the improvement of current treatment regimens. 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 4246. doi:10.1158/1538-7445.AM2011-4246