Abstract
It is hypothesised that Wilms tumour (WT) results from aberrant renal development due to its embryonic morphology, associated undifferentiated precursor lesions (termed nephrogenic rests) and embryonic kidney-like chromatin and gene expression profiles. From the study of overgrowth syndrome-associated WT, germline dysregulation was identified in the imprinted region at 11p15 affecting imprinted genes IGF2 and H19. This is also detected in ~70% sporadic cases, making this the most common somatic molecular aberration in WT. This review summarises the critical discussion at an international workshop held under the auspices of The European Network for Cancer Research in Children and Adolescents (ENCCA) consortium, where the potential for drug development to target IGF2 and the WT epigenome was debated. Here, we consider current cancer treatments which include targeting the IGF pathway and the use of methylation agents alone or in combination with other drugs in clinical trials of paediatric cancers. Finally, we discuss the possibility of the use of these drugs to treat patients with WT.
Highlights
Wilms tumour (WT) or nephroblastoma is the most frequent renal tumor of childhood affecting one in 10,000 children, with a peak incidence between two and three years of age [1]
In WT cell lines growing in the kidney environment, the use of the IGF1R inhibitor NVP-AEW541 resulted in growth inhibition associated with down-regulation of PI3K and mitogen activated protein kinase (MAPK) pathways and down-regulation of cell cycle control genes CCNA2 and CCNB1, with drug efficacy dependent on the levels of phosphorylated IGF1R [56]
It is clear that epigenetic alterations play a key role in a significant fraction of WTs and result in LOI at H19/IGF2 [33]
Summary
Wilms tumour (WT) or nephroblastoma is the most frequent renal tumor of childhood affecting one in 10,000 children, with a peak incidence between two and three years of age [1]. We discuss the subset of WTs with epigenetic aberrations at 11p15 resulting in activation of the IGF signaling pathway and the therapeutic opportunities provided by targeting either the IGF pathway or the epigenome.
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