Radio-Resistance and DNA Repair in Pediatric Diffuse Midline Gliomas

Abstract

Malignant gliomas (MG) are among the most prevalent and lethal primary intrinsic brain tumors. Although radiotherapy (RT) is the most effective nonsurgical therapy, recurrence is universal. Dysregulated DNA damage response pathway (DDR) signaling, rampant genomic instability, and radio-resistance are among the hallmarks of MGs, with current therapies only offering palliation. A subgroup of pediatric high-grade gliomas (pHGG) is characterized by H3K27M mutation, which drives global loss of di- and trimethylation of histone H3K27. Here, we review the most recent literature and discuss the key studies dissecting the molecular biology of H3K27M-mutated gliomas in children. We speculate that the aberrant activation and/or deactivation of some of the key components of DDR may be synthetically lethal to H3K27M mutation and thus can open novel avenues for effective therapeutic interventions for patients suffering from this deadly disease.

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

“…Cell cycle checkpoints play a critical role in sensing DNA damage and consequently mobilizing DNA-repair proteins, as well as halting cell cycle progression to allow time for DNA-repair ( 75 ). In general, the absence of these checkpoint kinases or downstream components causes continued cell division in the presence of DNA damage, typically leading to mitotic catastrophe and cell death ( 75 ).…”

“…Cell cycle checkpoints play a critical role in sensing DNA damage and consequently mobilizing DNA-repair proteins, as well as halting cell cycle progression to allow time for DNA-repair ( 75 ). In general, the absence of these checkpoint kinases or downstream components causes continued cell division in the presence of DNA damage, typically leading to mitotic catastrophe and cell death ( 75 ). To improve radiosensitivity in tumor cells, researchers have tried to mimic such events by abrogating cell cycle checkpoint activity as a possible therapeutic strategy in various cancer types, including pHGG ( 25 – 32 ).…”

“…To improve radiosensitivity in tumor cells, researchers have tried to mimic such events by abrogating cell cycle checkpoint activity as a possible therapeutic strategy in various cancer types, including pHGG ( 25 – 32 ). Of note, this strategy may be of particular interest in pHGG that already possess aberrations in cell cycle checkpoints, such as TP53 mutations, as these tumor cells heavily rely on the remaining checkpoints to repair RT-induced DNA damage ( 19 , 75 ). Furthermore, various studies indicate that pHGGs contain a considerable number of quiescent glioma stem cells (GSCs) intrinsically resistant to RT due to constitutive activation of cell cycle checkpoints and associated high DNA-repair efficiency ( 76 , 77 ).…”

Advanced Pediatric Diffuse Pontine Glioma Murine Models Pave the Way towards Precision Medicine

“…p38 MAPK is activated in both H3.3K27M and H3.1K27M cultured cells with H3.1K27M tumor cells more sensitive to p38 MAPK inhibition [ 49 ]. WNT [ 49 , 53 ], mTOR [ 53 , 54 ] and RTK-RAS-PI3K signaling pathways [ 53 , 55 ] were also active in both tumor subtypes. Interestingly, H3.1K27M and H3.3K27M DIPGs have their own associated mutations as summarized in Figure 1 .…”

The potential value of dequalinium chloride in the treatment of cancer: Focus on malignant glioma

“…As the most malignant type of glioma, GBM has tended to comprehensive treatments in recent years with a combination of surgery, radiotherapy and chemotherapy 3 . However, the overall prognosis of GBM is still poor as it has a high resistance to apoptosis and rampant genomic instability 4‐6 . The average survival time is 16 months, the 2‐year survival rate is only 25%–30%, and the 5‐year survival rate is less than 5% 2,7,8 .…”