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Pediatric high-grade glioma: aberrant epigenetics and kinase signaling define emerging therapeutic opportunities

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Abstract

Introduction

Supratentorial pediatric high-grade gliomas (pHGGs) are aggressive malignancies that lack effective treatment options. Deep genomic sequencing by multiple groups has revealed that the primary alterations unique to pHGGs occur in epigenetic and kinase genes. These mutations, fusions, and deletions present a therapeutic opportunity by use of small molecules targeting epigenetic modifiers and kinases that contribute to pHGG growth.

Methods

Using a targeted search of the pre-clinical literature and clinicaltrials.gov for kinase and epigenetic pathways in pHGG, we collectively describe how these mechanisms are being targeted in pre-clinical animal models and in current clinical trials, as well as propose unexplored therapeutic possibilities for future investigations.

Results

Relevant pHGG kinases are targetable by several FDA-approved or clinical-stage kinase inhibitors, including altered BRAF/MET/NTRK/ALK and wild-type PI3K/EGFR/PDGFR/VEGF/AXL. Epigenetic proteins implicated in pHGG are also clinically targetable and include histone erasers, writers and readers such as HDACs, demethylases LSD1/JMJD3, methyltransferase EZH2, chromatin reader bromodomains, and chromatin remodeler subunit BMI-1. Crosstalk between these pathways can occur involving kinases such as EGFR and AMPK interacting with epigenetic modifiers such as HDACs or EZH2. Single agent trial results of kinase inhibitors or epigenetic targets alone are underwhelming and hampered by poor pharmacokinetics, adaptive resistance, and broad inclusion criteria.

Conclusions

The genetic and phenotypic diversity of pHGGs is now well characterized after large-scale sequencing studies on patient tissue. However, clinical treatment paradigms have not yet shifted in response to this information. Combination therapies targeting multiple kinases or epigenetic targets may hold more promise, especially if attempted in selected patient populations with hemispheric pHGG tumors and relevant targeted therapeutic biomarkers.

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Funding

The authors acknowledge support from the MD Anderson Cancer Center CPRIT-CURE Training Program (to Y.S.), the Center for Cancer Epigenetics at M.D. Anderson and Schissler Foundation Fellowship (to C.P.B.), and from the National Institutes of Health: R21 NS093387 (to J.C.); R61 NS NS111058 (to J.C.) (ii) Brain Tumor SPORE P50 CA127001 (Developmental Research Project to JC).

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  1. Yusha Sun and Cavan P. Bailey have contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics – Research, MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 853, Houston, TX, 77030, USA

    Yusha Sun, Cavan P. Bailey & Joya Chandra

  2. Department of Pediatrics, MD Anderson Cancer Center, Houston, TX, USA

    Zsila Sadighi & Wafik Zaky

  3. Department of Epigenetics and Molecular Carcinogenesis, MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 853, Houston, TX, 77030, USA

    Joya Chandra

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  1. Yusha Sun
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Correspondence to Joya Chandra.

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Sun, Y., Bailey, C.P., Sadighi, Z. et al. Pediatric high-grade glioma: aberrant epigenetics and kinase signaling define emerging therapeutic opportunities. J Neurooncol 150, 17–26 (2020). https://doi.org/10.1007/s11060-020-03546-0

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