Advances in Research of Adult Gliomas

Finch, Alina; Solomou, Georgios; Wykes, Victoria; Pohl, Ute; Bardella, Chiara; Watts, Colin

doi:10.3390/ijms22020924

Cited by 44 publications

(35 citation statements)

References 214 publications

(176 reference statements)

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“…GBM harbors different cell types with somatic mutations that may confer different sensitivity to treatments. Therefore, resistance to therapy is not homogeneous within the tumor and depends on the molecular signatures of specific cells [156]. It is most likely that current therapeutic approaches only eliminate the sensitive tumor cell fraction, whereas the other cell sub-populations remain intact and result in relapse [155].…”

Section: Intra-tumor Heterogeneity and Tumor Microenvironment: Two Obstacles For Targeted Therapiesmentioning

confidence: 99%

“…These immune cells-that account for almost 50% of the tumor mass-secrete factors that create a continuously evolving environment, together with hypoxia and availability of nutrients. Thus, interactions between cancer cells and the fluctuating tumor microenvironment modifies epigenetic regulation and gene expression, affecting its heterogeneity and constant evolution [156].…”

Section: Intra-tumor Heterogeneity and Tumor Microenvironment: Two Obstacles For Targeted Therapiesmentioning

confidence: 99%

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Targeting Protein Kinase C in Glioblastoma Treatment

et al. 2021

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Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor and is associated with a poor prognosis. Despite the use of combined treatment approaches, recurrence is almost inevitable and survival longer than 14 or 15 months after diagnosis is low. It is therefore necessary to identify new therapeutic targets to fight GBM progression and recurrence. Some publications have pointed out the role of glioma stem cells (GSCs) as the origin of GBM. These cells, with characteristics of neural stem cells (NSC) present in physiological neurogenic niches, have been proposed as being responsible for the high resistance of GBM to current treatments such as temozolomide (TMZ). The protein Kinase C (PKC) family members play an essential role in transducing signals related with cell cycle entrance, differentiation and apoptosis in NSC and participate in distinct signaling cascades that determine NSC and GSC dynamics. Thus, PKC could be a suitable druggable target to treat recurrent GBM. Clinical trials have tested the efficacy of PKCβ inhibitors, and preclinical studies have focused on other PKC isozymes. Here, we discuss the idea that other PKC isozymes may also be involved in GBM progression and that the development of a new generation of effective drugs should consider the balance between the activation of different PKC subtypes.

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Section: Intra-tumor Heterogeneity and Tumor Microenvironment: Two Obstacles For Targeted Therapiesmentioning

confidence: 99%

Section: Intra-tumor Heterogeneity and Tumor Microenvironment: Two Obstacles For Targeted Therapiesmentioning

confidence: 99%

Targeting Protein Kinase C in Glioblastoma Treatment

et al. 2021

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“…Glioblastoma (GBM), the deadliest brain cancer, has a very poor prognosis that has not improved in the past 35 years [1][2][3]. The current clinical therapeutic approaches require new drug creations based on the latest technologies and knowledge of the GBM biology.…”

Section: Introductionmentioning

confidence: 99%

Multifunctional Nanopolymers for Blood–Brain Barrier Delivery and Inhibition of Glioblastoma Growth through EGFR/EGFRvIII, c-Myc, and PD-1

et al. 2021

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Glioblastoma (GBM) is the most prevalent primary brain cancer in the pediatric and adult population. It is known as an untreatable tumor in urgent need of new therapeutic approaches. The objective of this work was to develop multifunctional nanomedicines to treat GBM in clinical practice using combination therapy for several targets. We developed multifunctional nanopolymers (MNPs) based on a naturally derived biopolymer, poly(β-L-malic) acid, which are suitable for central nervous system (CNS) treatment. These MNPs contain several anticancer functional moieties with the capacity of crossing the blood–brain barrier (BBB), targeting GBM cells and suppressing two important molecular markers, tyrosine kinase transmembrane receptors EGFR/EGFRvIII and c-Myc nuclear transcription factor. The reproducible syntheses of MNPs where monoclonal antibodies are replaced with AP-2 peptide for effective BBB delivery were presented. The active anticancer inhibitors of mRNA/protein syntheses were Morpholino antisense oligonucleotides (AONs). Two ways of covalent AON-polymer attachments with and without disulfide bonds were explored. These MNPs bearing AONs to EGFR/EGFRvIII and c-Myc, as well as in a combination with the polymer-attached checkpoint inhibitor anti-PD-1 antibody, orchestrated a multi-pronged attack on intracranial mouse GBM to successfully block tumor growth and significantly increase survival of brain tumor-bearing animals.

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“…Glioma is the most frequent primary tumour of the central nervous system [ 1 ]. Because of anatomical particularity and highly aggressive biological behavior, glioma is considered to be one of the most devastating cancers.…”

Section: Introductionmentioning

confidence: 99%

“…Because of anatomical particularity and highly aggressive biological behavior, glioma is considered to be one of the most devastating cancers. Despite the substantial progress made in research on glioma in the past decades, the prognosis of most glioma patients remains dismal [ 1 , 2 ]. Therefore, it is an urgent need to further reveal the mechanism of glioma carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

An insertion variant of MGMT disrupts a STAT1 binding site and confers susceptibility to glioma

Huang

Yan

et al. 2021

Cancer Cell Int

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Background O6-methylguanine-DNA methyltransferase (MGMT) is a pivotal enzyme for repairing DNA alkylation damage. Epigenetic modification of MGMT has been well known as a promising prognostic biomarker for glioma. However, the significance of genetic variations of MGMT in glioma carcinogenesis has not been fully elucidated. Methods The associations between expression quantitative trait loci (eQTLs) of MGMT and glioma susceptibility were evaluated in a case–control study of 1056 individuals. The function of susceptibility locus for glioma was explored with a set of biochemical assays, including luciferase reporter gene, EMSA and supershift EMSA, ChIP, and siRNA knockdown. Results We found that rs11016798 TT genotype was associated with a significantly decreased risk of glioma (OR = 0.57, 95% CI 0.39–0.85; P = 0.006). Stratification analyses indicated that the association between rs11016798 and glioma was more pronounced in males (OR = 0.62, 95% CI 0.40–0.97; P = 0.035), older subjects (OR = 0.46, 95% CI 0.27–0.80; P = 0.006), WHO grade IV glioma (OR = 0.58, 95% CI 0.35–0.96; P = 0.033), and IDH wildtype glioma (OR = 0.43, 95% CI 0.21–0.88; P = 0.022). We characterized an insertion variant rs10659396 in the upstream of MGMT as a causative variant. The risk allele rs10659396 ins allele was demonstrated to downregulate MGMT expression by disrupting a STAT1 binding site. Knockdown of STAT1 remarkably attenuated MGMT expression. Moreover, the rs10659396 allele-specific positive correlation was observed between the expression of STAT1 and MGMT in population. Conclusions The study demonstrates that an insertion variant of MGMT rs10659396 confers susceptibility to glioma by downregulating MGMT expression through disrupting a STAT1 binding site. Graphic abstract

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Advances in Research of Adult Gliomas

Cited by 44 publications

References 214 publications

Targeting Protein Kinase C in Glioblastoma Treatment

Targeting Protein Kinase C in Glioblastoma Treatment

Multifunctional Nanopolymers for Blood–Brain Barrier Delivery and Inhibition of Glioblastoma Growth through EGFR/EGFRvIII, c-Myc, and PD-1

An insertion variant of MGMT disrupts a STAT1 binding site and confers susceptibility to glioma

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