Abstract 3891: Hornerin: a novel, non-VEGF mediated human tumor angiogenic protein.

Abstract

Abstract Angiogenesis is vital to the growth, progression and ultimately metastasis of tumors. As such, many therapies have attempted to eradicate tumors through anti-angiogenic strategies. Most current and past preclinical and clinically approved therapies focus on the vascular endothelial growth factor (VEGF) pathway. Unfortunately, these VEGF therapies have not shown much success, leading oncologists and scientists to become pessimistic about the usefulness of targeting angiogenesis as an anti-tumor strategy. Compensatory pathways may explain the lack of efficacy. Therapies against novel and/or non-VEGF proteins could hold the key to effective anti-angiogenic cancer therapies. Therefore, we used an in vivo phage display screen to find new, non-VEGF mediated angiogenic proteins. After phage selection, non-VEGF binding phage clones were identified by screening on human umbilical vein endothelial cells (HUVEC) treated with tumor conditioned media, VEGF conditioned media or vehicle control. Those that bound tumor conditioned media, but not VEGF conditioned media were selected for binding partner identification via functional proteomics pioneered in our lab. The binding partner of one clone was identified as hornerin, a previously unknown player in tumor angiogenesis. Subsequent validation of hornerin by mRNA expression, immunocytochemistry and immunohistochemistry showed that hornerin was indeed not induced by VEGF. Hornerin expression was 7-fold more in resected human PDAC tumor vasculature than adjacent normal pancreatic vasculature. Interestingly, hornerin expression was also detected in tumor cells of resected human PDAC and 20 other types of tumors, providing a potential new biomarker of pancreatic and other cancers. A functional role in angiogenesis was confirmed by intratumoral injection of short siRNA against endothelial hornerin; treated tumor growth was static and tumor vessels displayed a more physiologic phenotype. Combination therapy consisting of siRNA against hornerin and a VEGF inhibitor (AV-951) produced additive reduction of tumor growth, consistent with the existence of separate and/or compensatory pathways. The discovery of novel, non-VEGF mediated angiogenic proteins provides the potential to develop therapies that synergize with current anti-VEGF therapies. One such protein, hornerin was identified by our in vivo phage screen and shown to be functionally important in angiogenesis. Future studies include identifying the growth factor responsible for endothelial expression, understanding hornerin's mechanism and role in pathologic angiogenesis, and designing new therapeutic strategies. Citation Format: Marc E. Seaman, Kimberly A. Kelly. Hornerin: a novel, non-VEGF mediated human tumor angiogenic protein. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3891. doi:10.1158/1538-7445.AM2013-3891