scholarly journals Current Trends in Targeted Therapies for Glioblastoma Multiforme

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Fumiharu Ohka ◽  
Atsushi Natsume ◽  
Toshihiko Wakabayashi
Keyword(s):  
Glioblastoma Multiforme ◽  
Dna Methyltransferase ◽  
Clinical Settings ◽  
Future Perspectives ◽  
Aggressive Therapy ◽  
Methylguanine Dna Methyltransferase ◽  
Current Trends ◽  
Dismal Prognosis ◽  
The Central Nervous System ◽  
Molecular Targeting Agents

Glioblastoma multiforme (GBM) is one of the most frequently occurring tumors in the central nervous system and the most malignant tumor among gliomas. Despite aggressive treatment including surgery, adjuvant TMZ-based chemotherapy, and radiotherapy, GBM still has a dismal prognosis: the median survival is 14.6 months from diagnosis. To date, many studies report several determinants of resistance to this aggressive therapy: (1)O6-methylguanine-DNA methyltransferase (MGMT), (2) the complexity of several altered signaling pathways in GBM, (3) the existence of glioma stem-like cells (GSCs), and (4) the blood-brain barrier. Many studies aim to overcome these determinants of resistance to conventional therapy by using various approaches to improve the dismal prognosis of GBM such as modifying TMZ administration and combining TMZ with other agents, developing novel molecular-targeting agents, and novel strategies targeting GSCs. In this paper, we review up-to-date clinical trials of GBM treatments in order to overcome these 4 hurdles and to aim at more therapeutical effect than conventional therapies that are ongoing or are about to launch in clinical settings and discuss future perspectives.

scholarly journals Molecular and Circulating Biomarkers of Brain Tumors

2021 ◽  
Vol 22 (13) ◽  
pp. 7039
Author(s):  
Wojciech Jelski ◽  
Barbara Mroczko
Keyword(s):  
Brain Tumors ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Extracellular Vesicles ◽  
Dna Methyltransferase ◽  
Growth Factor Receptor ◽  
Response To Treatment ◽  
Liquid Biopsies ◽  
Methylguanine Dna Methyltransferase ◽  
The Central Nervous System

Brain tumors are the most common malignant primary intracranial tumors of the central nervous system. They are often recognized too late for successful therapy. Minimally invasive methods are needed to establish a diagnosis or monitor the response to treatment of CNS tumors. Brain tumors release molecular information into the circulation. Liquid biopsies collect and analyze tumor components in body fluids, and there is an increasing interest in the investigation of liquid biopsies as a substitute for tumor tissue. Tumor-derived biomarkers include nucleic acids, proteins, and tumor-derived extracellular vesicles that accumulate in blood or cerebrospinal fluid. In recent years, circulating tumor cells have also been identified in the blood of glioblastoma patients. In this review of the literature, the authors highlight the significance, regulation, and prevalence of molecular biomarkers such as O6-methylguanine-DNA methyltransferase, epidermal growth factor receptor, and isocitrate dehydrogenase. Herein, we critically review the available literature on plasma circulating tumor cells (CTCs), cell-free tumors (ctDNAs), circulating cell-free microRNAs (cfmiRNAs), and circulating extracellular vesicles (EVs) for the diagnosis and monitoring of brain tumor. Currently available markers have significant limitations.While much research has been conductedon these markers, there is still a significant amount that we do not yet understand, which may account for some conflicting reports in the literature.

scholarly journals MGMT promoter gene methylation and neurological scale improvement in glioma: a cohort study

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 139
Author(s):  
Pricilla Yani Gunawan ◽  
Andi Asadul Islam ◽  
Julius July ◽  
Ilhamjaya Patelongi ◽  
Agussalim Bukhari ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Assessment Tool ◽  
Gene Methylation ◽  
Methylguanine Dna Methyltransferase ◽  
Neurological Improvement ◽  
Nano Scale ◽  
Primary Brain Tumours ◽  
Dismal Prognosis ◽  
Mgmt Promoter ◽  
Promoter Gene

Background: Glioma is one of the most common primary brain tumours and conveys a dismal prognosis despite aggressive treatment. Several biomarkers have been studied in the hope of yielding better diagnostic accuracy and improving patient management. Besides survival, functional and neurological disability are concerns that have no lesser importance. In 2017, a disease-specific assessment tool – the Neurologic Assessment in Neuro-Oncology (NANO) scale – was developed to measure neurologic function in neuro-oncology cases. We sought to determine biomarkers that might be associated with neurological scale improvement in glioma patients.  Methods: Glioma grade II-IV patients were recruited from three major hospitals in Jakarta-Tangerang. Isocitrate dehydrogenase (IDH) mutation and O6-methylguanine-DNA methyltransferase (MGMT) promoter gene methylation were tested, as well as patients’ neurological function before surgery and three months after. Improvement in neurological scale (NANO scale) was considered positive if there was a decrement of ≥1 of the scale.  Results: There were 54 patients included in the study. Mean age was 43.63 (14.723) years old, and 61.1% were male. As much as 16 (29.6%) carried a mutation in codon 132 of the IDH1 gene, and 33 (61.1%) were MGMT methylated. Median NANO scale score before and three months after surgery was 4 (0-12) and 3 (0-12), respectively. Neurological improvement was found in 44 (81.5%) of the patients. Among patients with MGMT promoter gene methylation, 90.9% showed neurological improvement (p=0.035; OR=5; 95%CI 1.122-22.272).  Conclusions: Gliomas with MGMT promoter gene methylation are more likely to show neurological improvement three months after surgery.

scholarly journals O(6)-Methylguanine-DNA Methyltransferase Is a Novel Negative Effector of Invasion in Glioblastoma Multiforme

2012 ◽  
Vol 11 (11) ◽  
pp. 2440-2450 ◽  
Author(s):  
Manik Chahal ◽  
Bassam Abdulkarim ◽  
Yaoxian Xu ◽  
Marie-Christine Guiot ◽  
Jacob C. Easaw ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Dna Methyltransferase ◽  
Methylguanine Dna Methyltransferase

Current Translational Insights into MGMT Methylation Regulating Temozolomide Sensitivity and Resistance in Glioblastoma Multiforme

2020 ◽  
Vol 17 (2) ◽  
pp. 76-93 ◽  
Author(s):  
Ishmeet Gulati ◽  
Harsh Patel ◽  
Bala Prabhakar ◽  
Sujit Nair
Keyword(s):  
Dna Repair ◽  
Glioblastoma Multiforme ◽  
Dna Methyltransferase ◽  
Methylguanine Dna Methyltransferase ◽  
Drug Regulator ◽  
Ethnic Variability ◽  
Molecular Aspects ◽  
Functional Relevance

Background: Temozolomide is used as frontline chemotherapy in the management of glioblastoma multiforme (GBM); however, its clinical utility is limited by the occurrence of significant resistance, majorly caused due to direct DNA repair. O6- methylguanine-DNA-methyltransferase (MGMT), a DNA repair protein, mediates this direct repair pathway and reverses the activity of temozolomide. Methods: We characterize and underscore the functional relevance and molecular aspects of MGMT in the development of sensitivity/resistance to temozolomide treatment. We review early translational, as well as clinical, evidence for the role of MGMT in mediating temozolomide resistance in vitro in cell lines, in vivo in small animals as well as in GBM patients. Results: Various approaches have been delineated to mitigate MGMT-induced temozolomide resistance. The most promising means in discovery biology appears to be the co-administration of MGMT inhibitors such as O6 benzyl guanine or lomeguatrib. Surprisingly, the validation of these pharmacologic inhibitors to assess the reversal of chemoresistance by appropriately designed safety and efficacy trials in combination with temozolomide is yet to be demonstrated. Conclusions: Taken together, given the regulation of temozolomide resistance by MGMT, intermediate and late discovery groups may focus their efforts on pharmacologic inhibition of MGMT, singly or in combination with radiotherapy or immunotherapy, to combat temozolomide resistance in GBM patients. In addition, one may speculate that the combined clinical use of temozolomide with a drug regulator-approved MGMT inhibitor as well as an immune checkpoint inhibitor such as nivolumab may prove beneficial. Future studies may also investigate any inter-ethnic variability in population pharmacogenetics of MGMT and pharmacometric approaches to optimize cancer precision medicine.

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