Bromodomain and Extra-Terminal Protein Inhibitors: Biologic Insights and Therapeutic Potential in Pediatric Brain Tumors

Abstract

Pediatric brain tumors have surpassed leukemia as the leading cause of cancer-related death in children. Several landmark studies from the last two decades have shown that many pediatric brain tumors are driven by epigenetic dysregulation within specific developmental contexts. One of the major determinants of epigenetic control is the histone code, which is orchestrated by a number of enzymes categorized as writers, erasers, and readers. Bromodomain and extra-terminal (BET) proteins are reader proteins that bind to acetylated lysines in histone tails and play a crucial role in regulating gene transcription. BET inhibitors have shown efficacy in a wide range of cancers, and a number have progressed to clinical phase testing. Here, we review the evidence for BET inhibitors in pediatric brain tumor experimental models, as well as their translational potential.

Keywords: BET inhibitor; atypical teratoid rhabdoid tumor; diffuse intrinsic pontine glioma; embryonal tumor with multilayer rosettes; ependymoma; epigenetics; medulloblastoma; pediatric brain tumors.

Figure 1

BET protein expression in the central nervous system. (A) Human bulk RNA expression from the GTex database, clustered by brain tissue type [34] (B) Single-cell RNA sequencing atlas of the developing mouse brain showing ubiquitous BRD4 expression throughout cell types of the developing central nervous system [35,36].