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Review
. 2021 Apr 1:11:662209.
doi: 10.3389/fonc.2021.662209. eCollection 2021.

Radiosensitization in Pediatric High-Grade Glioma: Targets, Resistance and Developments

Dennis S Metselaar  1   2 , Aimée du Chatinier  1 , Iris Stuiver  2 , Gertjan J L Kaspers  1   2 , Esther Hulleman  1
Affiliations
Review

Radiosensitization in Pediatric High-Grade Glioma: Targets, Resistance and Developments

Dennis S Metselaar et al. Front Oncol. .

Abstract

Pediatric high-grade gliomas (pHGG) are the leading cause of cancer-related death in children. These epigenetically dysregulated tumors often harbor mutations in genes encoding histone 3, which contributes to a stem cell-like, therapy-resistant phenotype. Furthermore, pHGG are characterized by a diffuse growth pattern, which, together with their delicate location, makes complete surgical resection often impossible. Radiation therapy (RT) is part of the standard therapy against pHGG and generally the only modality, apart from surgery, to provide symptom relief and a delay in tumor progression. However, as a single treatment modality, RT still offers no chance for a cure. As with most therapeutic approaches, irradiated cancer cells often acquire resistance mechanisms that permit survival or stimulate regrowth after treatment, thereby limiting the efficacy of RT. Various preclinical studies have investigated radiosensitizers in pHGG models, without leading to an improved clinical outcome for these patients. However, our recently improved molecular understanding of pHGG generates new opportunities to (re-)evaluate radiosensitizers in these malignancies. Furthermore, the use of radio-enhancing agents has several benefits in pHGG compared to other cancers, which will be discussed here. This review provides an overview and a critical evaluation of the radiosensitization strategies that have been studied to date in pHGG, thereby providing a framework for improving radiosensitivity of these rapidly fatal brain tumors.

Keywords: glioma; pediatric high-grade glioma (pHGG); radio-enhancement; radioresistance; radiosensitizer; radiotherapy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Clinical advantages of radiosensitizers in pHGG.
Figure 2
Figure 2
p53 and PPM1D are central regulators of radiation sensitivity in pHGG.
Figure 3
Figure 3
DNA damage repair and PARP are vital against ROS-induced DNA breaks in pHGG.
Figure 4
Figure 4
Growth factor receptor activation and downstream PI3K/mTOR signaling are pivotal regulators of RT sensitivity and pHGG survival.
Figure 5
Figure 5
Condensed chromatin structures suppress DNA-repair machineries and induce RT sensitivity in pHGG.
Figure 6
Figure 6
Considerations for improved clinical translation of pre-clinical radiosensitizers in pHGG.
See this image and copyright information in PMC

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