Abstract
Simple SummaryTherapeutic targeting of Wnt has long been suggested for gastrointestinal (GI) cancer treatment because deregulation of Wnt signaling is associated with GI cancers. However, therapeutic targeting of Wnt is still challenging because of the pleiotropic roles of Wnt signaling in the human body. Thus, targeting strategies of Wnt signaling are continuously evolving. The current flows of targeting Wnt signaling for cancer treatment are focused on increasing the specificity of drugs and combinatory treatment with other cancer drugs that minimize side effects and increase efficacy. Additionally, increased knowledge about the β-catenin paradox has expanded the cases that can be treated with Wnt targeting therapy, not strictly considering Wnt upstream and downstream mutations. Here, we discuss these evolving views of targeting Wnt signaling and describe examples of current clinical trials.Wnt signaling governs tissue development, homeostasis, and regeneration. However, aberrant activation of Wnt promotes tumorigenesis. Despite the ongoing efforts to manipulate Wnt signaling, therapeutic targeting of Wnt signaling remains challenging. In this review, we provide an overview of current clinical trials to target Wnt signaling, with a major focus on gastrointestinal cancers. In addition, we discuss the caveats and alternative strategies for therapeutically targeting Wnt signaling for cancer treatment.
Highlights
Conserved Wnt signaling was initially identified in Drosophila (Wingless) and the mammalian system (Int-1) [1,2]
Wnt/Ca2+ signaling pathway, the binding of WNT-FZDs activates phospholipase C (PLC), which in turn triggers the release of Ca2+ from intracellular stores and the activation of effectors such as calcium- and calmodulin-dependent protein kinase II (CAMKII), protein kinase C (PKC), and calcineurin (CaN) [10,26]
CK1 and glycogen synthase kinase 3 (GSK3) activators likely reduce the level of β-catenin that translocates into the nucleus, inactivating Wnt signaling. pyrvinium, a CK1 activator that binds to the C-terminal regulatory domain of its isoform CK1A1, has been introduced, but it has not been evaluated in clinical trials (Table 3) [117]
Summary
Conserved Wnt signaling was initially identified in Drosophila (Wingless) and the mammalian system (Int-1) [1,2]. The manipulation of Wnt signaling has gained attention as a means of disease treatment and prevention [7,8] It has been confirmed in in vitro and in vivo cancer studies that targeting Wnt signaling has drastic tumor-suppressing effects, no targeted drugs have been successively advanced to clinical applications to date [7,8,9]. This is mainly because Wnt signaling plays essential roles in maintaining a Cancers 2020, 12, 3638; doi:10.3390/cancers12123638 www.mdpi.com/journal/cancers. We discuss current views on therapeutically targeting Wnt signaling and describe related clinical trials in gastrointestinal (GI)
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