Diffuse intrinsic pontine glioma: current insights and future directions

Abstract

Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain tumor and the leading cause of brain tumor-related death in children. As several clinical trials over the past few decades have led to no significant improvements in outcome, the current standard of care remains fractionated focal radiation. Due to the recent increase in stereotactic biopsies, tumor tissue availabilities have enabled our advancement of the genomic and molecular characterization of this lethal cancer. Several groups have identified key histone gene mutations, genetic drivers, and methylation changes in DIPG, providing us with new insights into DIPG tumorigenesis. Subsequently, there has been increased development of in vitro and in vivo models of DIPG which have the capacity to unveil novel therapies and strategies for drug delivery. This review outlines the clinical characteristics, genetic landscape, models, and current treatments and hopes to shed light on novel therapeutic avenues and challenges that remain.

Keywords: Diffuse intrinsic pontine glioma; Disease models; Molecular genetics; Neuro-oncology; Neurosurgery; Pediatrics; Therapeutics.

Fig. 1

T2-weighted sagittal pediatric brain MRI. Characteristic diagnostic T2-weighted MRI of pediatric DIPG. Note brainstem which demonstrates a diffuse expansile hyperintense lesion in the pons (arrow). These tumors are surgically unresectable due to their poorly circumscribed border and highly eloquent location. Where safe-entry zones are obeyed and neuromonitoring is employed, incisional biopsies under direct observation can be performed

Fig. 2

Representative histology of pediatric DIPG. a Hematoxylin & eosin stain of pediatric DIPG acquired post-mortem, note diffusely infiltrative tumor cells amidst a background matrix of neuropil. b Immunohistochemical staining of the same sample using antibody directed to the H3K27M epitope. The sample is strongly positive. c Immunohistochemical staining of mutant p53, a common co-occurring mutation in DIPG. Note sparser staining than H3K27M in panel b

Fig. 3

Drug targets and treatments of pediatric DIPG. DIPGs are characterized by the K27M mutation that occurs in histone H3. Therapies which target the epigenome including histone deacetylase inhibitors such as panobinostat (a) and histone demethylase inhibitors such as GSK-J4 (b) have been demonstrated to be effective in clinical trials. Furthermore, residual PRC2 activity has been shown to be required for proliferation and thus EZH2 inhibitors such as tazemetostat (c) has been effective in treating these tumors

Fig. 4

Targetable transcriptional dependencies in DIPGs. DIPGs can also be targeted pharmacologically at the DNA level by leveraging the transcriptional dependencies of the tumor. Transcriptional disruption has been demonstrated to reduce tumor growth via bromodomain (a) or CDK7 (b) inhibition using JQ1 or THZ1, respectively