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

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.

Targeting Cell Cycle Checkpoint Kinases to Overcome Intrinsic Radioresistance in Brain Tumor Cells

“…Several clinical phase I-II trials of checkpoint kinase inhibitors in combination with RT and CT in solid tumors or leukemia have been published or are ongoing, but a comprehensive review included only two ongoing trials on brain tumors [124]. A recent review discussed molecular targets in the treatment of high-grade pediatric glioma, but no clinical studies on cell cycle checkpoint kinase inhibitors were listed [125].…”

Impact of Chromatin Dynamics and DNA Repair on Genomic Stability and Treatment Resistance in Pediatric High-Grade Gliomas

“…Finally, it is noteworthy that the H3.3 and H3.1 mutant histones can be found associated with genetic alterations/mutations expected to perturb DNA repair (reviewed by Pedersen et al [ 22 ] and Metselaar et al [ 21 ]). For instance, Mackay et al [ 3 ] reported that 60% of the 1000 pHGGs characterized in their integrative genomic analysis contained genetic alterations in DNA repair genes, including HR genes and Fanconi anemia genes involved in the protection/restart of replication forks and DNA crosslink repair [ 186 ].…”

“…Targeting DNA repair pathway addictions, through inhibition of components of the DDR, including modulation of cell cycle and mitotic progression, and genetic stability, has emerged as an important therapeutic approach against many cancers [ 221 , 222 , 223 , 224 ]. At the same time, our catalogue of small molecule inhibitors targeting DNA repair is expanding rapidly [ 225 , 226 , 227 , 228 ] while novel targets are being discovered for the sensitization of glioma cells to radio- and chemotherapy [ 21 , 22 ]. These include RAD52 whose depletion led to TMZ hypersensitivity in GBM cells [ 64 ].…”

“…For pHGG patients with sus-tentorial locations, radiotherapy follows surgical resection, which tends to be extensive, and is associated at least with DNA alkylating agents like temozolomide (TMZ) [ 16 ]. In thalamic pHGGs and DIPGs, targeted therapies are nowadays proposed concomitantly to irradiation and prolonged until progression [ 17 , 18 , 19 , 20 , 21 ]. However, contrasting with our understanding of their molecular biology, there has been little improvement in the treatment of pHGGs where the development of tumor resistance driven by complex DNA repair pathways severely limits the efficiency of genotoxic chemotherapy and ionizing radiation (IR) [ 21 , 22 ].…”

Population-based analysis of radiation-induced gliomas after cranial radiotherapy for childhood cancers

“…Tremendous progress has been made over time to limit both dose and field of radiation exposure in order to minimize damage to healthy cells, which can lead to growth impairment, cognitive deficits, and secondary malignancies. 11 Despite these strides in RT technique, some degree of inherent risk remains, especially when a larger tumor or larger portion of the brain requires irradiation.…”