Abstract 354: BBI-608 modulates stemness, angiogenesis and enhances the efficacy of chemoradiotherapy in pre-clinical models of pancreatic cancer

Background: The transcription factor signal transducer and activator of transcription 3 (STAT-3) is constitutively activated in pancreatic ductal adenocarcinoma (PDAC) and signaling via this pathway regulates a diverse set of cellular processes including stemness, angiogenesis and sensitization to chemo or radiotherapy. Given the potential for BBI608 to elicit effects on multiple oncogenic cellular pathways including STAT-3, we hypothesized that BBI608 can sensitize pancreatic cell lines to the effects of 5FU and ionizing radiation. Methods: The combined effects of BBI-608 and chemoradiotherapy (5-FU + IR) were evaluated in human (MIA PaCa-2, PANC-1) and murine (PANC-02) PDAC cell lines using a clonogenic assay. Effects on the expression of cell surface markers associated with stemness (EGFR, CD24, and CD44) in MIA PaCa-2 cell lines in vitroand in vivo were examined by flow cytometry. Modulation of pSTAT3 and VEGF, key pro-angiogenic factors, were studied via Western blot. Using media from MIA PaCa-2 and PANC-1 cell lines following treatment, egg CAM assays were also performed to evaluate the effects of the tested drugs on angiogenesis (quantification was performed by AngioQuant software). The MIA PaCa-2 cell line was tested for activity to BBI-608, 5-FU + IR, alone and in combination, using an in vivo tumor xenograft model. Results: The combination of BBI-608 and chemoradiotherapy significantly (p