Developing drugs that target the Wnt pathway: recent approaches in cancer and neurodegenerative diseases

Abstract

Wnt/β-catenin signaling is an evolutionarily conserved pathway that has a crucial role in embryonic and adult life. Dysregulation of Wnt/β-catenin pathway has been associated with various diseases, including cancer and neurodegenerative disorders, including Parkinson's disease (PD). Several molecular components of the signaling have been proposed as innovative targets for cancer therapy, and very recently, some of them have been also evaluated as potential therapeutic targets for PD. Areas covered: This review focuses on the role of Wnt/β-catenin pathway in the pathogenensis of cancer and PD, examining some recent therapeutic approaches that are ongoing in preclinical and clinical studies. The possibilities that this signaling offers for diagnosis and prognosis of neoplastic diseases, and the concerns of targeting this pathway are also discussed. Expert opinion: Despite the stimulating results obtained in preclinical studies on cancer and other disease models, the clinical experience with Wnt modulators is still in its infancy, and is mainly restricted to anticancer therapy. Even with concerns of the safety of drugs targeting Wnt signaling, the attention of researchers worldwide is increasing to this issue in terms of their therapeutic potential for diseases such as PD, for which no cure exists.

Towards the first targeted therapy for triple-negative breast cancer: Repositioning of clofazimine as a chemotherapy-compatible selective Wnt pathway inhibitor

“…β-catenin revealed a striking change of the pattern of its intracellular distribution upon clofazimine treatment ( Figure 4A). In control tumors, the vast majority of the cells displayed a strong cytoplasmic pattern correlating well with the high levels of activity of Wnt signaling in these cells in the growing tumor [31,45]. Upon clofazimine treatment, a dramatic increase was seen in the number of cells losing cytoplasmic β-catenin and exclusively showing the membrane β-catenin staining pattern, typical for low Wnt signaling levels, with the plasma membrane pool of β-catenin mediating Wnt-independent cell-cell contact function [45] ( Figure 4A).…”

“…In control tumors, the vast majority of the cells displayed a strong cytoplasmic pattern correlating well with the high levels of activity of Wnt signaling in these cells in the growing tumor [31,45]. Upon clofazimine treatment, a dramatic increase was seen in the number of cells losing cytoplasmic β-catenin and exclusively showing the membrane β-catenin staining pattern, typical for low Wnt signaling levels, with the plasma membrane pool of β-catenin mediating Wnt-independent cell-cell contact function [45] ( Figure 4A). To account for the heterogeneity of IOWA-1T xenograft tumors, we quantified the slides for the relative number of cells divided into four subtypes by the observed level of membrane and cytoplasmic β-catenin ( Figure 4B) as well as performed slide scoring ( Figure 4C) followed by statistical analysis.…”

Atrial Natriuretic Peptide Acts as a Neuroprotective Agent in in Vitro Models of Parkinson’s Disease via Up-regulation of the Wnt/β-Catenin Pathway

“…The knowledge on the role of Wnt/β-catenin signaling in neurodegenerative diseases, and in particular in PD, is still in its infancy, and there are not any ongoing clinical studies specific on this issue, but only data concerning some preclinical therapeutic approaches, performed on cellular and animal models ( Serafino et al, 2017 ). The majority of papers published on this issue aim to demonstrate as the pharmacological activation of β-catenin signaling, by Wnt1 or Wnt1-like agonists ( Wei et al, 2013 ) or by GSK inhibitors ( L’Episcopo et al, 2011a ; Zhou et al, 2016 ), has neuroprotective capacity against DA neuron-specific toxins or is able to prevent loss of mDA neurons in the substantia nigra and to ameliorate motor symptoms in animal models of PD ( L’Episcopo et al, 2011a ).…”

“…In this state, up-regulation of active GSK-3β results in the phosphorylation and rapid degradation of β-catenin and increases DA neuron vulnerability, degeneration, and apoptosis ( L’Episcopo et al, 2014 ). Therefore, targeting Wnt signaling could be an effective strategy for neuroprotection/repair in PD ( Parish and Arenas, 2007 ; L’Episcopo et al, 2011a , 2014 ; Arenas, 2014 ; Dai et al, 2014 ; Serafino et al, 2017 ).…”

Tumor PDCD1LG2 (PD-L2) Expression and the Lymphocytic Reaction to Colorectal Cancer

“…Our study design (49,50) and population-based database allowed us to rigorously investigate the association of tumor PDCD1LG2 expression with lymphocytic reaction to colorectal cancer, controlling for multiple potential confounders. In addition, our colorectal cancer specimens were collected from a large number of hospitals in diverse settings across the U.S., which increases the generalizability of our findings.…”