Abstract 390: Correlation of the effects of antiangiogenic agents aflibercept (VEGF Trap) and anti-Dll4 antibody on tumor vascular perfusion and tumor growth

Abstract

Abstract Anti-angiogenic treatments are becoming widely used in several major cancer types. Most experimental and clinical development to date has focused on the VEGF pathway, although other signaling pathways, including Dll4-Notch, are also now being explored. However, clinical development for anti-angiogenic therapy has been hindered by a lack of tumor response biomarkers. In this study, we sought to correlate long-term tumor growth responses following blockade of VEGF or Dll4 with rapid effects on tumor vascular perfusion. Using VEGF Trap (aflibercept) and a blocking Dll4 antibody, we compared two tumors that differ widely in their long-term growth responses to each agent: C6 rat glioma tumors (anti-Dll4 resistant, aflibercept sensitive) and HT1080 human fibrosarcoma (anti-Dll4 sensitive, aflibercept resistant), both grown subcutaneously in SCID/CB17 mice. Tumor vascular perfusion was assessed using contrast-enhanced micro-ultrasound at 24 hr after treatment with aflibercept, anti-Dll4 Ab, or the combination, and tumor growth was measured during the course of prolonged twice-weekly treatments. We found that aflibercept treatment rapidly decreased tumor vascular perfusion in C6 tumors (36%) and produced an extended delay in tumor growth (8 days to reach 500mm3). In contrast, anti-Dll4 antibody produced no significant decrease in perfusion of C6 tumors at 24 hr after treatment, and a less dramatic delay in tumor growth (5 days to reach 500mm3). In HT1080 tumors, anti-Dll4 Ab dramatically decreased perfusion (38%), as well as causing a prolonged growth delay (20 days to reach 300mm3), whereas aflibercept caused neither a decrease in perfusion nor growth in these tumors. Unexpectedly, combination treatment with aflibercept and anti-Dll4 was most potent in both tumor types at reducing tumor perfusion and inhibiting tumor growth. Analysis of vascular density by CD31 immunohistochemistry at 24 hr after treatment revealed a decrease in C6 (57% and 31%) and HT1080 (28% and 19%) upon single agent aflibercept and combination treatment, respectively, while anti-Dll4 increased apparent vascular density of C6 tumors (31%) but produced no change in HT1080 tumors. Taken together, these data show that changes in tumor perfusion, but not in vessel density, correlate with long-term tumor responses to aflibercept and anti-Dll4, thus suggesting that decreases in tumor perfusion could be a rapid response biomarker for efficacy of anti-angiogenic therapies. 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 390.