Angiopoietin-2 (ANG2/ANGPT2) is a proangiogenic factor that promotes endothelial-cell survival and growth by activating the TIE2 receptor. We and others have shown that ANG2 blockade inhibits tumor angiogenesis and progression in mouse models of cancer. However, it is unclear whether ANG2 may limit tumor sensitivity to vascular-endothelial growth factor (VEGF)-targeted therapies. By employing mouse tumor models that are either sensitive or insensitive to VEGF inhibition, we found that the efficacy of VEGF signalling blockade may be limited by the adaptive upregulation of ANG2 in the resistant tumors. Indeed, combined ANG2/VEGF signaling blockade suppressed tumor angiogenesis and progression in anti-VEGF-resistant tumors, without eliciting increased tumor invasion or metastasis. These findings clearly strengthen the clinical rationale for co-targeting ANG2 and VEGF in tumors that develop resistance to VEGF inhibition. Notably, a minority of the tumors revascularized after VEGF/ANG2 blockade, showing adaptive resistance to the double antiangiogenic treatment. Because we noted an increase of tumor-associated macrophages (TAMs) in association with resistance to dual VEGF/ANG2 blockade, we have explored the opportunity to combine effective antiangiogenic therapy with pharmacological TAM depletion. The results of these studies will be presented at the meeting.

Citation Format: Michele De Palma. Overcoming tumor resistance to VEGF blockade by co-targeting ANG2/TIE2 signaling and macrophages. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr IA15. doi:10.1158/1538-7445.CHTME14-IA15

©2015 American Association for Cancer Research.
2015