scholarly journals Histone-Mutant Glioma: Molecular Mechanisms, Preclinical Models, and Implications for Therapy

2020 ◽  
Vol 21 (19) ◽  
pp. 7193 ◽  
Author(s):  
Maya S. Graham ◽  
Ingo K. Mellinghoff
Keyword(s):  
Targeted Therapies ◽  
Molecular Mechanisms ◽  
Malignant Gliomas ◽  
High Grade Glioma ◽  
High Grade ◽  
Cancer Death ◽  
Preclinical Models ◽  
Molecular Alterations ◽  
Potential Impact ◽  
Pediatric High Grade Glioma

Pediatric high-grade glioma (pHGG) is the leading cause of cancer death in children. Despite histologic similarities, it has recently become apparent that this disease is molecularly distinct from its adult counterpart. Specific hallmark oncogenic histone mutations within pediatric malignant gliomas divide these tumors into subgroups with different neuroanatomic and chronologic predilections. In this review, we will summarize the characteristic molecular alterations of pediatric high-grade gliomas, with a focus on how preclinical models of these alterations have furthered our understanding of their oncogenicity as well as their potential impact on developing targeted therapies for this devastating disease.

scholarly journals Molecular Biology in Pediatric High-Grade Glioma: Impact on Prognosis and Treatment

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Daniela Rizzo ◽  
Antonio Ruggiero ◽  
Maurizio Martini ◽  
Valentina Rizzo ◽  
Palma Maurizi ◽  
...  
Keyword(s):  
Molecular Biology ◽  
Targeted Therapies ◽  
Malignant Gliomas ◽  
Molecular Targets ◽  
High Grade Glioma ◽  
High Grade ◽  
Genetic Abnormalities ◽  
High Grade Gliomas ◽  
The Impact ◽  
Pediatric High Grade Glioma

High-grade gliomas are the main cause of death in children with brain tumours. Despite recent advances in cancer therapy, their prognosis remains poor and the treatment is still challenging. To date, surgery followed by radiotherapy and temozolomide is the standard therapy. However, increasing knowledge of glioma biology is starting to impact drug development towards targeted therapies. The identification of agents directed against molecular targets aims at going beyond the traditional therapeutic approach in order to develop a personalized therapy and improve the outcome of pediatric high-grade gliomas. In this paper, we critically review the literature regarding the genetic abnormalities implicated in the pathogenesis of pediatric malignant gliomas and the current development of molecularly targeted therapies. In particular, we analyse the impact of molecular biology on the prognosis and treatment of pediatric high-grade glioma, comparing it to that of adult gliomas.

scholarly journals Hemispherical Pediatric High-Grade Glioma: Molecular Basis and Therapeutic Opportunities

2020 ◽  
Vol 21 (24) ◽  
pp. 9654
Author(s):  
Santiago Haase ◽  
Fernando M. Nuñez ◽  
Jessica C. Gauss ◽  
Sarah Thompson ◽  
Emily Brumley ◽  
...  
Keyword(s):  
Cell Biology ◽  
High Grade Glioma ◽  
Cerebral Hemispheres ◽  
Clinical State ◽  
Molecular Characteristics ◽  
High Grade ◽  
Molecular Alterations ◽  
Current Therapies ◽  
Pediatric High Grade Glioma

In this review, we discuss the molecular characteristics, development, evolution, and therapeutic perspectives for pediatric high-grade glioma (pHGG) arising in cerebral hemispheres. Recently, the understanding of biology of pHGG experienced a revolution with discoveries arising from genomic and epigenomic high-throughput profiling techniques. These findings led to identification of prevalent molecular alterations in pHGG and revealed a strong connection between epigenetic dysregulation and pHGG development. Although we are only beginning to unravel the molecular biology underlying pHGG, there is a desperate need to develop therapies that would improve the outcome of pHGG patients, as current therapies do not elicit significant improvement in median survival for this patient population. We explore the molecular and cell biology and clinical state-of-the-art of pediatric high-grade gliomas (pHGGs) arising in cerebral hemispheres. We discuss the role of driving mutations, with a special consideration of the role of epigenetic-disrupting mutations. We will also discuss the possibilities of targeting unique molecular vulnerabilities of hemispherical pHGG to design innovative tailored therapies.

Anti-Apoptosis Mechanisms in Malignant Gliomas

2008 ◽  
Vol 26 (3) ◽  
pp. 493-500 ◽  
Author(s):  
David S. Ziegler ◽  
Andrew L. Kung ◽  
Mark W. Kieran
Keyword(s):  
Clinical Trial ◽  
Targeted Therapies ◽  
Malignant Gliomas ◽  
High Grade ◽  
Preclinical Models ◽  
Intrinsic Resistance ◽  
Apoptotic Pathway ◽  
Recent Advances ◽  
High Grade Gliomas ◽  
Fundamental Mechanism

Malignant gliomas are characterized by an intrinsic resistance to apoptosis. Increasing evidence suggests that this is a fundamental mechanism by which gliomas evade elimination when treated with both conventional and targeted therapies. In this review, we describe the multiple anti-apoptotic signals that have been demonstrated to be active in malignant gliomas. We describe the preclinical evidence that suggests that targeting those signaling anomalies can increase tumor responsiveness and enhance the elimination of gliomas in preclinical models. We discuss recent advances in translating pro-apoptotic compounds to clinical trial, and the potential for implementing agents that target the apoptotic pathway as a strategy for improving the outcomes for patients with high-grade gliomas.

Temozolomide in Malignant Gliomas of Childhood: A United Kingdom Children’s Cancer Study Group and French Society for Pediatric Oncology Intergroup Study

2002 ◽  
Vol 20 (24) ◽  
pp. 4684-4691 ◽  
Author(s):  
L. S. Lashford ◽  
P. Thiesse ◽  
A. Jouvet ◽  
T. Jaspan ◽  
D. Couanet ◽  
...  
Keyword(s):  
Response Rate ◽  
Objective Response ◽  
Malignant Gliomas ◽  
High Grade Glioma ◽  
Study Cohort ◽  
High Grade ◽  
French Society ◽  
Significant Treatment ◽  
Best Response ◽  
Daily Schedule

PURPOSE: To determine the response rate of the malignant gliomas of childhood to an oral, daily schedule of temozolomide. PATIENTS AND METHODS: A multicenter, phase II evaluation of an oral, daily schedule of temozolomide (200 mg/m2 on 5 consecutive days) was undertaken in children with relapsed or progressive, biopsy-proven, high-grade glioma (arm A) and progressive, diffuse, intrinsic brainstem glioma (arm B). Evidence of activity was defined by radiologic evidence of a sustained reduction in tumor size on serial magnetic resonance imaging scans. RESULTS: Fifty-five patients were recruited (34 to arm A and 21 to arm B) and received 215 cycles of chemotherapy. Grade 3/4 thrombocytopenia was the most frequent toxic event (7% of cycles). Prolonged myelosuppression resulted in significant treatment delays and dose reductions (17% and 22% of cycles, respectively). Two toxic deaths were documented and were related to myelosuppression and sepsis in one patient and pneumonia in a second. The overall (best) response rate was 12% for arm A (95% confidence interval [CI], 3 to 28 in the study cohort, and 2 to 31 for eligible patients) and 5% and 6%, respectively, for arm B (95% CI, 0 to 26 in the study cohort, and 0 to 27 for eligible patients). Stabilization of disease was also documented and was most noteworthy for brainstem gliomas, where two patients achieved both radiologic static disease and discontinued steroid medication. CONCLUSION: Despite moderate toxicity, objective response rates to temozolomide have been low, indicating that temozolomide has minimal activity in the high-grade gliomas of childhood.

scholarly journals HG-10 * HYPOXIA PATHWAY DRIVEN BY HIF-1ALPHA ARE PREDOMINANTLY INVOLVED IN PEDIATRIC HIGH GRADE GLIOMA AND REPRESENT PROMISING THERAPEUTIC TARGETS

2015 ◽  
Vol 17 (suppl 3) ◽  
pp. iii12-iii12
Author(s):  
C. Lasthaus ◽  
M. Litzler ◽  
C. Bour ◽  
D. Guenot ◽  
N. Entz-Werle
Keyword(s):  
Therapeutic Targets ◽  
High Grade Glioma ◽  
High Grade ◽  
Pediatric High Grade Glioma

scholarly journals Correlation of Metabolic Profiles of Plasma and Cerebrospinal Fluid of High-Grade Glioma Patients

Metabolites ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 133
Author(s):  
Artem D. Rogachev ◽  
Nikolay A. Alemasov ◽  
Vladimir A. Ivanisenko ◽  
Nikita V. Ivanisenko ◽  
Evgeniy V. Gaisler ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Molecular Mechanisms ◽  
High Grade Glioma ◽  
Diagnostic Procedures ◽  
Metabolic Profiles ◽  
High Grade ◽  
Wide Range ◽  
Targeted Screening ◽  
M Estimates ◽  
Metabolite Content

This work compares the metabolic profiles of plasma and the cerebrospinal fluid (CSF) of the patients with high-grade (III and IV) gliomas and the conditionally healthy controls using the wide-range targeted screening of low molecular metabolites by HPLC-MS/MS. The obtained data were analyzed using robust linear regression with Huber’s M-estimates, and a number of metabolites with correlated content in plasma and CSF was identified. The statistical analysis shows a significant correlation of metabolite content in plasma and CSF samples for the majority of metabolites. Several metabolites were shown to have high correlation in the control samples, but not in the glioma patients. This can be due to the specific metabolic processes in the glioma patients or to the damaged integrity of blood-brain barrier. The results of our study may be useful for the understanding of molecular mechanisms underlying the development of gliomas, as well as for the search of potential biomarkers for the minimally invasive diagnostic procedures of gliomas.

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