Abstract IA25: Therapies directed at the Wnt pathway

Abstract

Abstract The Wnt pathway represents a family of glycoproteins involved in proliferation, morphology, and migration, and dysregulation of the pathway is present in many cancers.1 Activating mutations, epigenetic events and autocrine activation of the Wnt pathway exists in many tumor types, and these alterations converge into sustained proliferation, increased tumorigenicity, and enhanced metastatic potential. The name “Wnt” comes from combining the drosophila patterning gene wingless and the homologous oncogene int1. There are three branches to the Wnt signaling pathway: the beta-catenin pathway (“canonical”); and the nonconical pathways Wnt/Ca2+ and Wnt/planar cell polarity (PCP). The canonical pathway becomes activated when Wnt ligand binds receptors which regulate nuclear beta-catenin, which in turn regulates critical transcription factors. The PCP pathway is mediated through the GTPases Rho and Rac involved in invasion, metastasis, and angiogenesis, whereas the Ca2+ pathway affects intracellular Ca2+ levels important for Ca2+ homeostasis, cell adhesion, and apoptosis. The focus of this discussion will be on the canonical beta-catenin pathway, which is more commonly implicated in cancer. The canonical pathway is driven by WNT ligands (WNT), which are a family of 19 glycoproteins that bind to multiple transmembrane receptors, including 10 members of the frizzled (FZD) family of G-protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) ROR1 and ROR2, and RTK-like protein kinases (RYKs) triggering downstream activation.2 The pathway is somewhat unusual in that it is regulated largely through a destruction complex containing adenomatous polyposis coli (APC), glycogen synthase kinase 3β (GSK3β), and Axin. The destruction complex ubiquitinates β-catenin and prevents its accumulation. Wnt stimulation leads to disruption of the destruction complex and β-catenin accumulation and localization to the nucleus. Cellular response is induced via gene transduction alongside the TCF/LEF (T-cell factor/lymphoid enhancing factor) transcription factors.3 Beyond the destruction complex, negative regulators of the WNT pathway include secreted Dickkopf (Dkk), WNT inhibitory Factor (WIF), and soluble frizzled-related proteins (sFRP). Porcupine (PORCN), a membrane bound O-acyltransferase that is required for WNT palmitoylation, secretion, and biologic activity acts as a positive regulator of the pathway. Pharmacologic strategies targeting the Wnt pathway include modulation of the ligand/receptor interface, stabilization of the degradation complex, or interference with β-Catenin dependent gene transcription.4-6 Phase I studies of several agents have been completed, with mostly acceptable patient tolerance but limited single-agent activity.5 Phase Ib/II studies, many including combination strategies, are underway in several tumor types. In this presentation, the current status and future directions of WNT inhibitors in solid tumors will be reviewed.