Abstract 1722: Hedgehog and Wnt crosstalk in pancreatic cancer

Abstract

Abstract Pancreatic cancer is the fourth leading cause of cancer-related death in the United States. It is characterized by a dense desmoplastic stroma that is thought to limit drug delivery and to contribute to the low response rate to chemo and targeted therapies. There are many pathways involved in the tumor-stroma communication, and Wnt and Hedgehog (Hh) signaling are amongst them. Both pathways are abnormally activated in pancreatic cancer by overexpression of their ligands and receptors, and both, although to a different extent, affect tumor and stromal cells. Disappointingly, in the clinic, Hh pathway inhibition using Smoothened (Smo) inhibitors did not improve patient outcomes, despite the strong anti-stromal activity of the compounds. During embryonic development, Hh signaling directly crosstalks with the Wnt pathway through the expression of secreted frizzled-related protein 1 (sFRP-1), a negative regulator of Wnt signaling. In cancer, the expression of sFRP-1, however, is frequently suppressed. Here, we show for the first time, that in pancreatic cancer, sFRP-1 is not only expressed, but that its expression is increased in the metastatic disease setting. Furthermore, Hh pathway inhibition using the Smo inhibitor GDC-0449 decreased sFRP-1 expression, and this was paralleled by an increase, or by maintenance of the elevated expression, of β-catenin target genes. In vivo, in a patient-derived xenograft (PDX) model of pancreatic cancer, treatment with GDC-0449 maintained elevated levels of nuclear β-catenin, and had no effect on tumor growth. To confirm the importance of the Hh-Wnt crosstalk in pancreatic cancer we compared the effects of the Smo inhibitior to those of an acetyl-CoA carboxylase 1(ACC1) inhibitor, which we recently developed (BAY ACC002), and which we have shown to block both Wnt and Hh signaling by inhibiting ligand lipidation. As in the case of GDC-0449, treatment of Capan-2 human pancreatic cancer cells in vitro with BAY ACC002, indeed, decreased sFRP-1 expression. However, unlike the Smo inhibitor, BAY ACC002 reduced the levels of β-catenin target genes. Furthermore, in vivo BAY ACC002 showed anti-tumor efficacy in several different xenograft models, whereas GDC-0449 showed no activity. Together, these data build evidence for a crosstalk between Hh and Wnt signaling in pancreatic cancer, and offer a novel approach to overcome the limitations observed with Smo inhibitors in the clinic. These results also highlight the benefit of a simultaneous inhibition of both pathways in order to achieve a sustained effect on both the tumor and the tumor stroma. Citation Format: Elissaveta Petrova, Arne Scholz, Juliane Paul, Andrea Sturz, Katja Haike, Franziska Siegel, Dominik Mumberg, Ningshu Liu. Hedgehog and Wnt crosstalk in pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1722.