Is Wilms tumor a candidate neoplasia for treatment with WNT/β-catenin pathway modulators?--A report from the renal tumors biology-driven drug development workshop

Abstract

The European Network for Cancer Research in Children and Adolescents consortium organized a workshop in Rome, in June 2012, on "Biology-Driven Drug Development Renal Tumors Workshop" to discuss the current knowledge in pediatric renal cancers and to recommend directions for further research. Wilms tumor is the most common renal tumor of childhood and represents a success of pediatric oncology, with cure rates of more than 85% of cases. However, a substantial minority (∼25%) responds poorly to current therapies and requires "high-risk" treatment or relapse. Moreover, the successfully treated majority are vulnerable to the late effects of treatment, with nearly one quarter reporting severe chronic health conditions by 25 years of follow-up. Main purposes of this meeting were to advance our understanding on the molecular drivers in Wilms tumor, their heterogeneity and interdependencies; to provide updates on the clinical-pathologic associations with biomarkers; to identify eligible populations for targeted drugs; and to model opportunities to use preclinical model systems and prioritize targeted agents for early phase clinical trials. At least three different pathways are involved in Wilms tumor; this review represents the outcome of the workshop discussion on the WNT/β-catenin pathway in Wilms tumorigenesis.

Figure 1

Canonical WNT/β-catenin signaling and inhibitors. (A) WNT—off state: In the absence of WNT ligands, the destruction complex (containing Axin, APC, WTX, GSK3 and CKI) promotes N-terminal phosphorylation of β-catenin. This leads to ubiquitin-mediated proteasomal degradation of β-catenin and keeps intracellular levels low. Meanwhile, TCF/LEF type transcription factors recruit Groucho and histone deacetylases to repress WNT target genes. (B) WNT—on state: once WNT ligands bind to FZ/LRP6 co-receptors, the cytoplasmic tail of LRP6 is phosphorylated, the β-catenin destruction complex is inhibited through recruitment of its components to the FZ/LRP/DVL complex. Consequently, β-catenin accumulates intracellularly, translocates to the nucleus, and displaces Groucho from TCF/LEF. This interaction promotes the transcription of WNT target genes. Inhibitors of the WNT/β-catenin pathway (depicted in red) are shown and include: 1) agents targeting WNTs: antibodies against WNTs; soluble WNT receptors; proteins acting like WNT inhibitory proteins (WIF) and secreted frizzled related proteins (SFRPs); 2) FZ receptor antibody; 3) LRP inhibitors, acting like the members of the Dickkopf (DKK) family; 4) compounds targeting the PDZ domain of Dishevelled (DVL), responsible of DVL/FZ interaction and signal transduction; 5) molecules which stabilize the Axin protein; 6) molecules that inhibit Porcupine (Porc), an enzyme essential for WNT lipidation and secretion; 7) β-catenin/TCF and β-catenin/CPB interaction antagonists