Wnt Self-Renewal Inhibitors

The Wnt/β-catenin pathway is another highly conserved pathway involved in cell growth and proliferation, as well as PaCSC self-renewal. In the canonical pathway, Wnt proteins that are modified by porcupine to become lipid-bound bind to frizzled receptor complexes and the co-receptor LRP5/6. The signal is then passed downstream via disheveled, which in its active state inhibits phosphorylation of β-catenin, allowing it to accumulate in the cytoplasm. β-catenin is then translocated to the nucleus, where it forms a transcriptional complex and acts on target genes. RNF43 and ZNRF3 were recently identified as Wnt target genes and negative feedback regulators that are inactivated in pancreatic adenocarcinoma (Zhan et al. 2017). Two regions of the pathway the researchers intend to target include upstream, such as porcupine and frizzled, and downstream between the interaction of β-catenin and its target genes. Small molecule inhibitors of porcupine such as LGK974 and ETC-159 have been highly effective in pancreatic cancer to block signaling (Novartis Pharmaceuticals 2018). The monoclonal antibody Vantictumab blocks frizzled receptors and has shown beneficial effects in treating pancreatic adenocarcinoma when combined with paclitaxel or gemcitabine (Messersmith et al. 2016). Additionally, the small molecule inhibitor PRI-724 has shown promising effects in blocking the interaction between β-catenin and its target genes (PRISM Pharma 2017). The researchers would like to include all of these in their treatment of halting the Wnt pathway, thereby stopping PaCSC self-renewal.