Epigenetic Targeted Therapy for Diffuse Intrinsic Pontine Glioma

Abstract

Diffuse intrinsic pontine glioma (DIPG) is a rare but uniformly fatal cancer of the brain, with peak incidence in children of 5-7 years of age. In contrast to most types of human cancer, there has been no significant improvement in treatment outcomes for patients with DIPG. Since DIPG occurs in the brainstem, a vital region of the brain, there are no surgical options for providing relief to patients, and chemotherapy as well as radiation therapy provide palliative relief at best. To date, more than 250 clinical trials evaluating radiotherapy along with conventional cytotoxic chemotherapy, as well as newer biologic agents, have failed to improve the dismal outcome when compared with palliative radiation alone. The recent discovery of somatic oncogenic histone gene mutations affecting chromatin regulation in DIPG has dramatically improved our understanding of the disease pathogenesis in DIPG, and these findings have stimulated the development of novel therapeutic approaches targeting epigenetic regulators for disease treatment. This review will discuss about the role of histone modification in chromatin machinery and epigenetic therapeutic strategies for the treatment of DIPG.

Keywords: DIPG; demethylation; histone; methylation; pediatric brain tumor.

Fig. 1

New epigenetic therapies for DIPGs. In DIPG, H3K27M mutations (histone H3.1 or H3.3) lead to hypomethylation of H3K27, which promotes a more accessible chromatin state characterized by H3K27 acetylation and aberrant gene expression (upper: Euchromatin). H3K27M mutations inhibits the major H3K27 methylase PRC2. Treatment of DIPG with K27 demethylase inhibitor GSKJ4 results in increased K27me2 and K27me3 and, reduced tumor growth (lower: Heterochromatin). Moreover, treatment with the non-specific HDAC inhibitor panobinostat demonstrated an increase in global H3 acetylation increasing/restoring H3K27me3 levels. In addition, competitive binding with BET bromodomain inhibitors prevents the interaction of BRD4 with acetylated histone, leading to the repression of BRD4 transcriptional targets and also limiting tumor growth. Reprinted by permission from Taylor & Francis Group, LLC: Epigenetics [January 6, Epub ahead of print], copyright 2017.