Diffuse intrinsic pontine glioma: molecular landscape and emerging therapeutic targets

Abstract

Purpose of review: Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brainstem malignancy. Despite advances in understanding of the molecular underpinnings of the tumor in the past decade, the dismal prognosis of DIPG has thus far remained unchanged. This review seeks to highlight promising therapeutic targets within three arenas: DIPG cell-intrinsic vulnerabilities, immunotherapeutic approaches to tumor clearance, and microenvironmental dependencies that promote tumor growth.

Recent findings: Promising therapeutic strategies from recent studies include epigenetic modifying agents such as histone deacetylase inhibitors, bromodomain and extra-terminal motif (BET) protein inhibitors, and CDK7 inhibitors. Tumor-specific immunotherapies are emerging. Key interactions between DIPG and normal brain cells are coming to light, and targeting critical microenvironmental mechanisms driving DIPG growth in the developing childhood brain represents a new direction for therapy.

Summary: Several DIPG treatment strategies are being evaluated in early clinical trials. Ultimately, we suspect that a multifaceted therapeutic approach utilizing cell-intrinsic, microenvironmental, and immunotherapeutic targets will be necessary for eradicating DIPG.

FIGURE 1.

Diffuse intrinsic pontine glioma is a heterogeneous tumor that lacks effective therapies. Eradicating this tumor may require a multifaceted approach with combinatorial therapies that target distinct tumor vulnerabilities. Here, we illustrate one therapeutic example in three distinct domains where studies have shown promising targeting of diffuse intrinsic pontine glioma. One cell-intrinsic therapy that targets the aberrant transcription resulting from H3K27M-mediated polycomb repressive complex-2 dysfunction is THZ1, an inhibitor of CDK7. CDK7 is responsible for phosphorylation of RNA pol II required for transcription initiation, and thus THZ1 may inhibit the increased transcription of diffuse intrinsic pontine glioma oncogenes that potentiates tumorigenesis. In immunotherapy, one of the most promising targets is the widely expressed diffuse intrinsic pontine glioma antigen GD2. Anti-GD2 chimeric antigen receptor T cells have demonstrated dramatic tumor clearance in xenograft models, and this strategy will be pursued in clinical trials. Diffuse intrinsic pontine glioma cells initiate and proliferate due to signals in the developing brain microenvironment, and strategies to inhibit protumorgenic signals will be important in containing tumor growth. Here, we illustrate the proliferation effect of neuronal-activity regulated neuroligin-3 secretion through the mammalian target of rapamycin (mTOR)/PI3K pathway. Inhibition of ADAM10 cleavage of neuroligin-3 prevents its activity-regulated secretion from neurons and oligodendrocyte precursor cells (OPCs) and causes a stark reduction in diffuse intrinsic pontine glioma proliferation. ADAM10 inhibitors will be used in future clinical trials for diffuse intrinsic pontine glioma. Diffuse intrinsic pontine glioma cells = neon green, neuron = pink, OPC = dark green, chimeric antigen receptor-T cell = purple, WT H3K27 histone = light blue, H3K27M histone = orange, active polycomb repressive complex-2 = dark blue, inactive polycomb repressive complex-2 = gray, ADAM10 inhibitor = dark blue hexagon, THZ1 (CDK7 inhibitor) = turquoise pentagon. Illustration created using Biorender.