Abstract 709: Angiogenic switch: novel therapeutic target for pancreatic cancer

Abstract

Abstract Background: Despite research efforts directed at early detection and treatment of pancreatic cancer (PC), the outlook for patients affected by this disease remains dismal. Angiogenesis is required for progression and metastasis of PC. An angiogenic switch, a shift of balance between pro-angiogenic and angiogenic state is a hallmark of cancer progression. The objective of this study was to investigate whether increased angiogenesis could be a predictor of PC occurrence and progression. Combinations of cytotoxic drugs led to increased activity and minimized resistance compared to single agents in tumor therapy. Thus, we investigated whether antiangiogenic treatment could be improved by combinations targeting different pathways using a combination of tyrosine kinase inhibitors sorafenib and erlotinib. Methods: We performed immunoblotting, flow cytometry, immunohistochemistry, immunocytochemistry and quantification of sub-cellular protein expression to quantitatively assesses protein expression of angiogenesis associated markers such as vascular endothelial growth factor (VEGF), VEGF receptor 1 (FLT-1), VEGF receptor 2 (FLK-1), VEGF receptor 3 (R3), neuropilin (NP-1), epidermal growth factor receptor (EGFR), matrix metalloproteinases (MMP) 2 and 9 during development and progression of PC and examined their correlations with chosen clinico-pathological parameters. Tissues, tumor lysates and sera from 1) a transgenic mouse model of pancreatic ductal adenocarcinoma (PDA) and 2) from a cohort of 80 human PC patients at various stages of PC and suitably matched control. Two human PC cell lines Panc-1 and MiaPaca-2 were used to study drug effects. Statistical analyses were performed using SAS version 9.2. Results: Disease stage was highly prognostic for outcome. A significant association was found between high expressions of MMP-2 (p < 0.04) and NP-1 (p < 0.0001) at earlier stage in tissue and serum both. VEGFR-3 showed higher expression in primary PC. EGFR was significantly higher in patients with distant metastases compared to non distant metastases and primary cancer (p < 0.0001). Sorafenib reduced cell viability in a dose and time-dependent manner, induced apoptosis and reduced expression of VEGF, FLK-1, c-raf and NP-1. The combination treatment showed synergistic effects on EGFR. Conclusions: Significantly higher expression of MMP-2 at earlier stage VS normal in tissue and serum, suggests that tumor expression of MMP2 is a marker of highly aggressive disease. However, higher expression of VEGF-R3 was seen on primary lesions, potentially implicating this receptor in initiation of lymphatic tumor spread. Combination therapies targeting multiple angiogenic pathways have synergistic activity and could help to avoid resistance to single inhibitors in tumor treatment. Further studies of the functional and clinical importance of these findings are warranted. 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 709. doi:1538-7445.AM2012-709