Abstract 5772: Antagonizing the CREB binding protein (CBP)/beta-catenin interaction sensitizes pancreatic cancer cells to chemotherapy

Abstract

Abstract Wnt/beta-catenin signaling plays an important role in the regulation of cell proliferation and differentiation, maintenance of stem cell pluripotency and cancer development. Using specific small molecular inhibitors, we have previously demonstrated that the critical mechanism differentiating between cell proliferation and cell differentiation is the switch of beta-catenin binding to the coactivator CBP or p300 respectively. In colorectal cancer, and hematologic malignancies with overt wnt/beta-catenin signaling activity, the small molecular inhibitor of CBP/beta-catenin enhances sensitivity to chemotherapy and tumor growth control. Although pancreatic cancers do not generally carry mutations in Wnt signaling regulators (e.g. APC, beta-catenin), recent studies indicate that Wnt/beta-catenin signaling promotes tumorigenesis in pancreatic cancer as well. Since pancreatic cancer is one of the most intrinsically resistant cancers to chemotherapy, the purpose of this study was to explore the effect of the small molecular CBP/beta-catenin inhibitor alone and in combination with standard chemotherapy in pancreatic cancer cell lines in vitro and in vivo. The combination of the small molecular inhibitor of CBP/beta-catenin with Gemcitabine or Erlotinib significantly inhibited cell proliferation of Panc-1, BxPC-3 and AsPC-1 pancreatic cancer cells in vitro. Anti-proliferative effects were seen with the combination of a small molecular CBP/beta-catenin antagonist and Gemcitabine concentrations as low as 1nM. qRT-PCR revealed a significant down regulation of the Wnt target genes Survivin and S100A4 which have been shown previously to be of prognostic relevance in pancreatic cancer patients. AsPC-1-Luc pancreatic cancer cells with stable transfected luciferase activity were implanted orthotopically into the pancreas of Nu/Nu mice and mice were randomized to either treatment with single agent small molecular CBP/beta-catenin inhibitor, Gemicitabine, Erlotinib or the combination of small molecular inhibitor and Gemcitabine or Erlotinib. Tumor engraftment and tumor growth were monitored once per week using the bioluminescence imaging system IVIS200. The data of the ongoing orthotopic tumor xenograft study show a beneficial therapeutic effect of the small molecular inhibitor in combination with chemotherapeutic and targeted agents. The results of our study indicate that the Wnt/beta-catenin pathway is an attractive therapeutic target in pancreatic cancer. In particular the inhibition of CBP/beta-catenin interaction using a small molecular inhibitor sensitizes pancreatic cancer cells to the chemotherapeutic agent Gemcitabine and EGFR-targeted therapy with Erlotinib in vitro. Ongoing in vivo experiments appear to be highly promising to confirm the in vitro results. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5772.