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- W1639844185 abstract "AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA2491 The Ras/Raf/MEK/Erk pathway plays an important role in gastrointestinal cancer. We hypothesized that this oncogenic pathway is also important in pancreatic cancer, despite activating B-Raf mutations are infrequent in this cancer entity. In addition, we sought to investigate whether dual inhibition of Raf and VEGFR2 could be a valid approach for molecular targeted therapy of pancreatic cancer. Pancreatic cancer cells (PCs) and endothelial cells (ECs) were used for experiments. Dual inhibition of Raf/VEGFR2 was achieved by using a small molecule inhibitor (NVP-AAL881; Novartis Oncology, USA). The Raf-inhibitory component and its effect on ECs was investigated by using a selective VEGFR2 inhibitor. Effects on signaling pathways were determined by Western blotting and impact on cell migration in Boyden chambers. Changes in VEGF were assessed by RT-PCR and ELISA. Effect of NVP-AAL881 on pancreatic cancer growth was investigated in an orthotopic model. Raf kinases were activated in PCs and in ECs. NVP-AAL881 reduced phospho-B-Raf in cancer cells, and diminished activation of MEK, Akt, and Erk. In addition, phospho-STAT3 was substantially reduced, suggesting that a Ras/Raf/JAK/STAT3 pathway can effectively be blocked. Moreover, dual-inhibition of Raf/VEGFR2 significantly reduced VEGF expression and impaired cancer cell migration. Importantly, besides blocking VEGF-induced Erk and Akt phosphorylation in ECs, NVP-AAL881 also led to inhibition of B-Raf, C-Raf and STAT3 phosphorylation. This effect was mediated independently of its VEGFR2 blockade. In addition, EC proliferation and cell migration were significantly reduced. In vivo, therapy with NVP-AAL881 significantly reduced orthotopic tumor growth (P<0.05) and VEGF expression in tumors. Dual-inhibition of Raf and VEGFR2 led to interference with oncogenic signaling pathways in vitro and reduced pancreatic cancer growth in vivo. Importantly, blocking Raf also elicited direct effects on endothelial cells, suggesting that tumor angiogenesis could also be impaired. Hence, targeting Raf and VEGFR2 appears to be a promising strategy for therapy of human pancreatic cancer." @default.
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- W1639844185 date "2008-05-01" @default.
- W1639844185 modified "2023-09-22" @default.
- W1639844185 title "Dual-inhibition of Raf kinase and VEGFR2 reduces pancreatic cancer growth trough direct effects on tumor cells and endothelial cells." @default.
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