Abstract
Pediatric high-grade glioma (pHGG) and brainstem gliomas are some of the most challenging cancers to treat in children, with no effective therapies and 5-year survival at ~2% for diffuse intrinsic pontine glioma (DIPG) patients. The standard of care for pHGG as a whole remains surgery and radiation combined with chemotherapy, while radiation alone is standard treatment for DIPG. Unfortunately, these therapies lack specificity for malignant glioma cells and have few to no reliable biomarkers of efficacy. Recent discoveries have revealed that epigenetic disruption by highly conserved mutations in DNA-packaging histone proteins in pHGG, especially DIPG, contribute to the aggressive nature of these cancers. In this review we pose unanswered questions and address unexplored mechanisms in pre-clinical models and clinical trial data from pHGG patients. Particular focus will be paid towards therapeutics targeting chromatin modifiers and other epigenetic vulnerabilities that can be exploited for pHGG therapy. Further delineation of rational therapeutic combinations has strong potential to drive development of safe and efficacious treatments for pHGG patients.
Highlights
Malignancies of the central nervous system (CNS) have been a constant challenge for clinicians and researchers alike
These tumors are classified by the World Health Organization (WHO) as either grade III or IV meaning that they are highly malignant tumors with characteristic findings such as hypercellularity, nuclear atypia, and high mitotic activity with or without microvascular proliferation and pseudopalisading necrosis [3]
HGG include a variety of heterogeneous lesions with differing histology, including anaplastic astrocytoma (WHO Grade III), glioblastoma (WHO grade IV) and diffuse midline glioma, H3 K27M variant (H3-K27M) mutant as the most common types
Summary
Efforts to amass tissue specimens from pHGG patients and apply DNA and RNA sequencing technology have reclassified pHGG pathology. It was later found that H3.1/3.3-K27M inactivation of PRC2 can enrich H3K27me at specific loci, causing either gene activation (hypo-H3K27me3) or gene suppression (enriched-H3K27me3) in unique pathways [21] These findings were recapitulated with additional insight into the role of DNA methylation as a consequence of H3.3-K27M, as well as observance of increased H3K27me in intergenic regions of the genome, suggesting a possible link with miRNA or lncRNA dysregulation in H3-mutated pHGG [22]. A key additional observation was increased presence on these same nucleosomes of bromodomain and extra-terminal motif (BET) proteins BRD1 and BRD4 which function to “read” histone acetylation marks [62] This suggests use of inhibitors of the BRD family as a therapeutic option in K27M-mutated DIPG, and the pan-BET inhibitor JQ1 has displayed anti-tumor efficacy in pre-clinical models [53,54] (Table 2). Given that the only positive in vivo data using HDAC inhibitors in pHGG utilized convection-enhanced delivery directly to the pons [66], alternative delivery strategies of small molecules and biologics to the dense tumor tissue may hold the key to successful pHGG therapy
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