Volume 102 Issue 2, February 2022

Vitamin D has recently emerged as a neurosteroid and a regulator of various physiological functions. It has been widely reported to promote tumor-suppressive effects, however this proposal remains controversial. This article reviews the anti-tumoral mechanisms of vitamin D in glioblastoma, current evidence of its therapeutic application as a supplement to standard chemotherapy, and its potential applications for cancer prevention; it endeavors to offer insight into new means of overcoming chemoresistance and improving glioma patient survival.

The 5th edition of WHO Classification of Tumors of the Central Nervous System adopted new molecular markers into the revised grading criteria of IDH-mutant and -wild-type astrocytoma, i.e., the CDKN2A/B homozygous deletion for IDH-mutant astrocytoma and the following three criteria for IDH-wild-type astrocytoma: the concurrent gain of whole chromosome 7 and loss of whole chromosome 10, TERT promoter mutations, and EGFR amplification, as independent molecular markers of the highest grade.

Cell-free DNA (cfDNA) profiling as liquid biopsy is of clinical utility in carcinomas of adult-onset. However, its application in childhood cancers, including brain tumors, has not been as extensively studied. In this article, we review the current status of applying cfDNA analysis for pediatric central nervous system neoplasms. Technical challenges, evidence for utility based on current literature, and potential future developments are discussed.

The mRNA expression levels of phospholipase Cγ1 (PLCG1) are much higher in IDH wild-type (IDHwt) lower-grade gliomas (LGGs) than in that of IDH mutant (IDHmut) LGGs. Higher PLCG1expression in IDHwt LGGs indicates poor clinical outcome. PLCG1 amplification may act as the key mechanism of PLCG1 upregulation. Depletion of PLCG1 expression can inhibits proliferation and invasion of IDHwt LGG cell lines in vitro and in vivo. The PLC inhibitor U73122 may therefore be a potential therapeutical agent for IDHwt LGGs.

The authors developed a deep learning model predictive of 1p/19q status from preoperative imaging in 555 lower-grade gliomas (LGG), and achieved an area under the curve (AUC) of 0.983 in the testing dataset. They reveal that developing deep learning imaging signatures could be a noninvasive tool for predicting molecular markers in LGG.

The authors examined 13 mismatch repair-deficient (MMRD)-associated primary brain tumors to determine molecular characteristics and biological behavior. MMRD occurred after chemotherapy and radiotherapy in two cases. The genetic profile of MMRD glioblastoma was different from that of conventional glioblastoma. Half of the MMRD-gliomas and all Lynch syndrome-associated GBMs were high in microsatellite instability. These tumors had high mutational burdens and tended to have shorter progression-free survival than glioma without MMRD.

The authors barcoded glioma-initiating cells (GIC) using combinations of virally encoded fluorophores. GIC show a strong tendency to form clonal populations over as few as two passages. Combined with stem cell marker phenotyping and computational analysis, they could trace the fate of such populations. This model presents an approach for rapid assessment of newly established GIC to assess tumour-specific vulnerabilities.

This study confirms the preservation of EZH2 overexpression in 22 patient-derived orthotopic xenograft models of pediatric brain tumors. The authors demonstrate the activity of an FDA-approved EZH2 inhibitor, tazemetostat, alone and in combination with radiation in a subset of the models, and identifies EZH2-negative cells as potential cause of therapy resistance.

Pharmacological inhibition of the serine synthesis pathway with a highly selective inhibitor NCT503 synergistically works with temozolomide in inhibiting O⁶-methylguanine DNA methyltransferase (MGMT)-positive glioblastoma cell growth and inducing apoptosis both in vitro and in vivo. Mechanistically, NCT503 treatment reduces MGMT expression possibly via Wnt/βcatenin pathway. Reactive oxygen species-mediated DNA damage is at least partially involved. Combinational administration of NCT503 and TMZ may represent a novel and promising treatment strategy to enhance TMZ efficacy in patients with MGMT-high glioblastoma.

Understanding of endothelial functions would be accelerated by methods for the specific isolation of these cells from archived human specimens. Here, the authors use the endothelial transcription factor Erg to isolate nuclei from mouse and human tissues, paving the way for high-throughput characterization of the function of endothelium in homeostasis and disease.