Abstract 1380: Mechanisms of resistance to antiangiogenic therapy in preclinical models of head and neck squamous cell carcinoma (HNSCC)

Abstract

Abstract Purpose: The Vascular Endothelial Growth Factor (VEGF) is ubiquitously expressed and targeted with FDA-approved agent bevacizumab in many types of cancer including colon, lung and renal carcinoma. In head and neck cancer, bevacizumab is under active clinical investigation. However, its efficacy in most cases is limited, with only modest response rates observed in the clinical trials. These incomplete drug responses suggest the presence of alternative signaling mechanisms that compensate for VEGF blockade. The proinflammatory cytokine, Interleukin 8 (IL-8) is known to promote tumor angiogenesis, and is coexpressed with VEGF in HNSCC. Hence, IL-8 signaling may be a possible mechanism of resistance to anti-VEGF therapy. Experimental Design: In this study, we assessed the efficacy of bevacizumab in preclinical HNSCC models to identify tumors that were sensitive or resistant to the treatment. In order to identify potential mediators of bevacizumab resistance, we evaluated the angiogenic profile of HNSCC cells from the non-isogenic pair of sensitive and resistant cell lines by performing angiogenesis antibody array. We further examined the potential contribution of IL-8 signaling to the in vivo growth of bevacizumab-resistant xenografts, using shRNA-mediated knockdown of the IL-8 gene. Results: HNSCC cell lines showed a range of response to bevacizumab in vivo. Interestingly, the resistant cell lines expressed high levels of proangiogenic factors including IL-8, IL-1a and VEGF compared to the sensitive cell lines. Further, combined inhibition of VEGF and IL-8 in the resistant xenografts resulted in a significant reduction in tumor volume and microvessel density compared to targeting VEGF alone. Conclusions: Our results indicate that HNSCC xenografts display a differential response to anti-VEGF therapy. IL-8 was the most differentially expressed protein in the angiogenic signature of the bevacizumab-resistant and sensitive cells. Finally, abrogation of IL-8 signaling sensitized the resistant xenografts to anti-VEGF therapy. These findings suggest that IL-8 may be associated with anti-VEGF resistance in HNSCC. Hence, co-targeting of VEGF and IL-8 may improve antiangiogenic therapeutic efficacy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1380. doi:1538-7445.AM2012-1380