AUTHOR=Leszczynska Katarzyna B. , Jayaprakash Chinchu , Kaminska Bozena , Mieczkowski Jakub 

TITLE=Emerging Advances in Combinatorial Treatments of Epigenetically Altered Pediatric High-Grade H3K27M Gliomas

JOURNAL=Frontiers in Genetics

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.742561

DOI=10.3389/fgene.2021.742561

ISSN=1664-8021

ABSTRACT=Somatic mutations in histone encoding genes result in gross alterations in the epigenetic landscape. Diffuse intrinsic pontine glioma (DIPG) is a pediatric high-grade glioma (pHGG) and one of the most challenging cancers to treat, with only 1% surviving for 5 years. Due to location in the brainstem, DIPGs are difficult to resect and rapidly turn into a fatal disease. Over 80% of DIPGs confer mutations in genes coding for histone 3 variants (H3.3 or H3.1/H3.2), with lysine to methionine substitution at the position 27 (H3K27M). This results in a global decrease in H3K27 trimethylation, increased H3K27 acetylation, and wide-spread oncogenic changes in gene expression. Epigenetics modifying drugs emerge as promissing candidates to treat DIPG, with histone deacetylase (HDAC) inhibitors taking the lead in pre-clinical and clinical studies. However, some data show evolving resistance of DIPGs to the most-studied HDAC inhibitor panobinostat and highlight the need to investigate its mechanism of action further. A new intense line of research is directed towards the simultaneous use of multiple inhibitors that could target epigenetically-induced changes in DIPG chromatin and enhance the anti-cancer response of single agents. In this review, we summarize the therapeutic approaches against H3K27M-expressing pHGGs focused on targeting epigenetic dysregulation and highlight promising combinatorial drug treatments. We assess effectiveness of the epigenetic drugs that are already in clinical trials in pHGGs. The constantly expanding understanding of the epigenetic vulnerabilities of H3K27M-expressing pHGGs opens new possibilities in providing tumor-specific targets and gives hope to find a cure for this deadly disease.