Abstract A18: The tankyrase inhibitor G007-LK inhibits small intestine Lgr5+ stem cell proliferation without altering tissue morphology

Abstract

Abstract Tankyrase enzymes play crucial roles in the Wnt signaling pathway, involved in the regulation of intestinal stem cells and tissue homeostasis. Aberrant Wnt signaling is known to cause intestinal cancers and the tankyrase inhibitor G007-LK has previously been shown to inhibit tumor growth in an APC-mutant colorectal cancer xenograft model. We have used in vivo models to address the effect of G007-LK on small intestine tissue homeostasis. The mice were treated for up to 3 weeks with the tankyrase inhibitor, without affecting the body mass or observed clinical condition of the mice. H&E staining of fixed small intestine tissue sections showed no significant differences in the general tissue morphology between control and G007-LK treated mice. In the presence of G007-LK, lineage tracing from the Lgr5+ intestinal stem cells was significantly reduced compared to control mice. When the G007-LK treatment was stopped two days prior to initiation of lineage tracing, there were no significant difference in the number of traced cells between the mice pretreated with G007-LK and untreated control group. Immunohistochemistry (IHC) staining for the proliferation marker Ki67 showed a slight reduction in the number of positive cells in the small intestine of the G007-LK treated compared to control mice. As expected, in the crypt base cells there was a reduction of nuclei staining positive for β-catenin in the G007-LK treated compared to control mice, suggesting repressed Wnt/β-catenin signaling. Taken together, our data show that the tankyrase inhibitor G007-LK is well tolerated by the mice. The tankyrase inhibitor reduced the proliferative activity of the small intestine Lgr5+ stem cells, without altering the general morphology or function of the tissue. Citation Format: Jens Henrik Norum, Ellen Skarpen, Andreas Brech, Raoul Kuiper, Jo Waaler, Stefan Krauss, Therese Sørlie. The tankyrase inhibitor G007-LK inhibits small intestine Lgr5+ stem cell proliferation without altering tissue morphology. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A18.