Association of plasma levetiracetam concentration, MGMT methylation and sex with survival of chemoradiotherapy-treated glioblastoma patients

Cucchiara, Federico; Luci, Giacomo; Giannini, Noemi; Giorgi, Filippo Sean; Orlandi, Paola; Banchi, Marta; Paolo, Antonello Di; Pasqualetti, Francesco; Danesi, Romano; Bocci, Guido

doi:10.1016/j.phrs.2022.106290

Cited by 4 publications

(3 citation statements)

References 43 publications

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“…Emerging studies have proved the methylation level of cancer-associated genes participate in the progression and treatment of cancers [ 26 ]. DNA methylation has been studied to be involved in some cellular processes [ 27 , 28 ].…”

Section: Resultsmentioning

confidence: 99%

The biological significance of cuproptosis-key gene MTF1 in pan-cancer and its inhibitory effects on ROS-mediated cell death of liver hepatocellular carcinoma

et al. 2023

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Metal regulatory transcription factor 1 (MTF1) has been reported to be correlated with several human diseases, especially like cancers. Exploring the underlying mechanisms and biological functions of MTF1 could provide novel strategies for clinical diagnosis and therapy of cancers. In this study, we conducted the comprehensive analysis to evaluate the profiles of MTF1 in pan-cancer. For example, TIMER2.0, TNMplot and GEPIA2.0 were employed to analyze the expression values of MTF1 in pan-cancer. The methylation levels of MTF1 were evaluated via UALCAN and DiseaseMeth version 2.0 databases. The mutation profiles of MTF1 in pan-cancers were analyzed using cBioPortal. GEPIA2.0, Kaplan–Meier plotter and cBioPortal were also used to explore the roles of MTF1 in cancer prognosis. We found that high MTF1 expression was related to poor prognosis of liver hepatocellular carcinoma (LIHC) and brain lower grade glioma (LGG). Also, high expression level of MTF1 was associated with good prognosis of kidney renal clear cell carcinoma (KIRC), lung cancer, ovarian cancer and breast cancer. We investigated the genetic alteration and methylation levels of MTF1 between the primary tumor and normal tissues. The relationship between MTF1 expression and several immune cells was analyzed, including T cell CD8 + and dendritic cells (DC). Mechanically, MTF1-interacted molecules might participate in the regulation of metabolism-related pathways, such as peptidyl-serine phosphorylation, negative regulation of cellular amide metabolic process and peptidyl-threonine phosphorylation. Single cell sequencing indicated that MTF1 was associated with angiogenesis, DNA repair and cell invasion. In addition, in vitro experiment indicated knockdown of MTF1 resulted in the suppressed cell proliferation, increased reactive oxygen species (ROS) and promoted cell death in LIHC cells HepG2 and Huh7. Taken together, this pan-cancer analysis of MTF1 has implicated that MTF1 could play an essential role in the progression of various human cancers.

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Section: Resultsmentioning

confidence: 99%

The biological significance of cuproptosis-key gene MTF1 in pan-cancer and its inhibitory effects on ROS-mediated cell death of liver hepatocellular carcinoma

et al. 2023

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“…Retrospective and prospective studies have previously identified potential prognostic and predictive factors grounded in sex differences. Sex differences have been noted in anti-epileptic management [ 70 ], chemotherapy [ 12 , 71 ], and immunotherapy [ 11 , 17 ] ( Table 3 ). Looking ahead at the potential future results of omic analyses will therefore involve looking back at current and previous trials wherein a biospecimen was/is being collected to examine where future conclusions may originate from ( Table 5 ) and how this bedside data connects to bench data, including tissue culture and animal studies.…”

Section: Omics and Biospecimen Analysismentioning

confidence: 99%

The Next Frontier in Health Disparities—A Closer Look at Exploring Sex Differences in Glioma Data and Omics Analysis, from Bench to Bedside and Back

et al. 2022

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Sex differences are increasingly being explored and reported in oncology, and glioma is no exception. As potentially meaningful sex differences are uncovered, existing gender-derived disparities mirror data generated in retrospective and prospective trials, real-world large-scale data sets, and bench work involving animals and cell lines. The resulting disparities at the data level are wide-ranging, potentially resulting in both adverse outcomes and failure to identify and exploit therapeutic benefits. We set out to analyze the literature on women’s data disparities in glioma by exploring the origins of data in this area to understand the representation of women in study samples and omics analyses. Given the current emphasis on inclusive study design and research, we wanted to explore if sex bias continues to exist in present-day data sets and how sex differences in data may impact conclusions derived from large-scale data sets, omics, biospecimen analysis, novel interventions, and standard of care management.

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“… 2 The current standard of care for GBM involves radiotherapy in combination with the DNA alkylating agent temozolomide (TMZ). 3 In 2005, a randomized controlled trial reported improved survival rates for patients with GBM who received TMZ in conjunction with radiotherapy, with patient survival increasing from 12.1 to 14.6 months. 4 Despite progress in both basic and clinical research, the blood-brain barrier limits the effectiveness of GBM therapies, resulting in uniformly poor median survival rates in the past few decades.…”

Section: Introductionmentioning

confidence: 99%

Suppression of ITPKB degradation by Trim25 confers TMZ resistance in glioblastoma through ROS homeostasis

Yan,

Zhou,

Chen

et al. 2024

Sig Transduct Target Ther

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Temozolomide (TMZ) represents a standard-of-care chemotherapeutic agent in glioblastoma (GBM). However, the development of drug resistance constitutes a significant hurdle in the treatment of malignant glioma. Although specific innovative approaches, such as immunotherapy, have shown favorable clinical outcomes, the inherent invasiveness of most gliomas continues to make them challenging to treat. Consequently, there is an urgent need to identify effective therapeutic targets for gliomas to overcome chemoresistance and facilitate drug development. This investigation used mass spectrometry to examine the proteomic profiles of six pairs of GBM patients who underwent standard-of-care treatment and surgery for both primary and recurrent tumors. A total of 648 proteins exhibiting significant differential expression were identified. Gene Set Enrichment Analysis (GSEA) unveiled notable alterations in pathways related to METABOLISM_OF_LIPIDS and BIOLOGICAL_OXIDATIONS between the primary and recurrent groups. Validation through glioma tissue arrays and the Xiangya cohort confirmed substantial upregulation of inositol 1,4,5-triphosphate (IP3) kinase B (ITPKB) in the recurrence group, correlating with poor survival in glioma patients. In TMZ-resistant cells, the depletion of ITPKB led to an increase in reactive oxygen species (ROS) related to NADPH oxidase (NOX) activity and restored cell sensitivity to TMZ. Mechanistically, the decreased phosphorylation of the E3 ligase Trim25 at the S100 position in recurrent GBM samples accounted for the weakened ITPKB ubiquitination. This, in turn, elevated ITPKB stability and impaired ROS production. Furthermore, ITPKB depletion or the ITPKB inhibitor GNF362 effectively overcome TMZ chemoresistance in a glioma xenograft mouse model. These findings reveal a novel mechanism underlying TMZ resistance and propose ITPKB as a promising therapeutic target for TMZ-resistant GBM.

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Association of plasma levetiracetam concentration, MGMT methylation and sex with survival of chemoradiotherapy-treated glioblastoma patients

Cited by 4 publications

References 43 publications

The biological significance of cuproptosis-key gene MTF1 in pan-cancer and its inhibitory effects on ROS-mediated cell death of liver hepatocellular carcinoma

The biological significance of cuproptosis-key gene MTF1 in pan-cancer and its inhibitory effects on ROS-mediated cell death of liver hepatocellular carcinoma

The Next Frontier in Health Disparities—A Closer Look at Exploring Sex Differences in Glioma Data and Omics Analysis, from Bench to Bedside and Back

Suppression of ITPKB degradation by Trim25 confers TMZ resistance in glioblastoma through ROS homeostasis

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