Targeting transcription in neuroblastoma: focus on the Core regulatory circuit.

Neuroblastoma, a sympathetic nervous system tumor, is known for its remarkable biological heterogeneity. Unlike other neurogenic malignancies driven by mutations, neuroblastoma carries a significant 'transcriptional burden.' Deregulation of transcription unveils in the course of the tumor's natural history, making the advanced stages of the disease intractable. Recent research investigated the molecular profiles of key neuroblastoma states: adrenergic (ADRN) and mesenchymal (MES). These categories are defined by core regulatory circuit (CRC) genes whose products (transcription factors) modulate a variety of malignant properties. This review analyzes fundamental mechanisms of regulation of CRC in neuroblastoma, focusing on transcriptional alterations as tentative therapeutic targets. We dissect differential CRC patterns in ADRN and MES states and discuss opportunities for therapeutic combinations targeting CRC along with other survival mechanisms. We emphasize the critical importance of combined CRC inactivation as a promising therapeutic avenue. This approach is substantiated by basic biological mechanisms largely demonstrated in experimental models. Although the detailed roles of CRC in individual clinical situations remain to be elucidated, interference with the subtype-specific patterns of CRC-dependent gene expression, together with inactivation of an additional survival factor(s), offers new opportunities for mechanism-based, personalized treatment.