scholarly journals Molecular features assisting in diagnosis, surgery, and treatment decision making in low-grade gliomas

2015 ◽  
Vol 38 (3) ◽  
pp. E2 ◽  
Author(s):  
Ricky Chen ◽  
Vijay M. Ravindra ◽  
Adam L. Cohen ◽  
Randy L. Jensen ◽  
Karen L. Salzman ◽  
...  
Keyword(s):  
Imaging Techniques ◽  
Molecular Genetic ◽  
Treatment Decision ◽  
Resonance Spectroscopy ◽  
Low Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
Genetic Event ◽  
Surgical Interventions ◽  
Low Grade Gliomas ◽  
Molecular Features

The preferred management of suspected low-grade gliomas (LGGs) has been disputed, and the implications of molecular changes for medical and surgical management of LGGs are important to consider. Current strategies that make use of molecular markers and imaging techniques and therapeutic considerations offer additional options for management of LGGs. Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes suggest a role for this abnormal metabolic pathway in the pathogenesis and progression of these primary brain tumors. Use of magnetic resonance spectroscopy can provide preoperative detection of IDH-mutated gliomas and affect surgical planning. In addition, IDH1 and IDH2 mutation status may have an effect on surgical resectability of gliomas. The IDH-mutated tumors exhibit better prognosis throughout every grade of glioma, and mutation may be an early genetic event, preceding lineage-specific secondary and tertiary alterations that transform LGGs into secondary glioblastomas. The O6-methylguanine-DNAmethyltransferase (MGMT) promoter methylation and 1p19q codeletion status can predict sensitivity to chemotherapy and radiation in low- and intermediate-grade gliomas. Thus, these recent advances, which have led to a better understanding of how molecular, genetic, and epigenetic alterations influence the pathogenicity of the different histological grades of gliomas, can lead to better prognostication and may lead to specific targeted surgical interventions and medical therapies.

Treatment of Adult Lower-Grade Glioma in the Era of Genomic Medicine

2016 ◽  
pp. 75-81 ◽  
Author(s):  
Susan M. Chang ◽  
Daniel P. Cahill ◽  
Kenneth D. Aldape ◽  
Minesh P. Mehta
Keyword(s):  
Molecular Genetic ◽  
Genomic Medicine ◽  
Genetic Alterations ◽  
World Health ◽  
Low Grade ◽  
Lower Grade ◽  
Cell Of Origin ◽  
Low Grade Gliomas ◽  
Molecular Features ◽  
Anaplastic Gliomas

By convention, gliomas are histopathologically classified into four grades by the World Health Organization (WHO) legacy criteria, in which increasing grade is associated with worse prognosis and grades also are subtyped by presumed cell of origin. This classification has prognostic value but is limited by wide variability of outcome within each grade, so the classification is rapidly undergoing dramatic re-evaluation in the context of a superior understanding of the biologic heterogeneity and molecular make-up of these tumors, such that we now recognize that some low-grade gliomas behave almost like malignant glioblastoma, whereas other anaplastic gliomas have outcomes comparable to favorable low-grade gliomas. This clinical spectrum is partly accounted for by the dispersion of several molecular genetic alterations inherent to clinical tumor behavior. These molecular biomarkers have become important not only as prognostic factors but also, more critically, as predictive markers to drive therapeutic decision making. Some of these, in the near future, will likely also serve as potential therapeutic targets. In this article, we summarize the key molecular features of clinical significance for WHO grades II and III gliomas and underscore how the therapeutic landscape is changing.

scholarly journals CBMT-10. MUTANT ISOCITRATE DEHYDROGENASE 1 INHIBITION INDUCES A UNIQUE MRS-DETECTABLE METABOLIC SIGNATURE IN LOW-GRADE GLIOMAS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi34-vi35
Author(s):  
Abigail Molloy ◽  
Aliya Lakhani ◽  
Chloé Najac ◽  
Elavarasan Subramani ◽  
Anne Marie Gillespie ◽  
...  
Keyword(s):  
Cell Lines ◽  
Isocitrate Dehydrogenase ◽  
Phase 1 ◽  
Genetically Engineered ◽  
Resonance Spectroscopy ◽  
Low Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
1H Mrs ◽  
Low Grade Gliomas ◽  
Non Invasive

Abstract Mutations in isocitrate dehydrogenase 1/2 (IDHmut) are reported in 70–90% of low-grade gliomas and secondary glioblastomas. IDHmut catalyzes the reduction of a-ketoglutarate (a-KG) to 2-hydroxyglutarate (2-HG), an oncometabolite that drives tumorigenesis. Inhibition of IDHmut is therefore a rapidly emerging therapeutic approach and IDHmut inhibitors such as AG-120 and AG-881 have shown promising results in phase 1 and 2 clinical studies. The goal of this study was to identify early non-invasive metabolic biomarkers of IDHmut inhibition that can serve to moniter response to these therapies. We used 1H and 13C magnetic resonance spectroscopy (MRS) to investigate the response of two genetically-engineered IDHmut cell lines (U87-based and normal human astrocyte-based) to AG-120 and AG-881 treatment. As expected, in both cell lines, our 1H-MRS data indicated that AG-120 and AG-881 induced a significant decrease in 2-HG. Interestingly however, we also observed a significant increase in phosphocholine and glutamate, pointing to broader changes in the metabolism of treated cells and a unique MRS signature. To further investigate the increase in glutamate induced by AG-120 and AG-881 in our models, we used 13C-MRS and quantified the flux of [1-13C] glucose and [3-13C] glutamine to 13C-labeled glutamate. Our results indicate that both AG-120 and AG-881 significantly increase the flux of 13C-labeled glutamine to 13C glutamate, while the flux of 13C-labeled glucose to 13C glutamate remained unchanged. Further studies are currently underway to explore the utility of using hyperpolarized [1-13C]-glutamine and hyperpolarized [1-13C]-a-KG for monitoring flux to glutamate and 2-HG, and to validate these probes as additional biomarkers of response to IDHmut inhibition. Taken together, our studies indicate that IDHmut inhibition induces a unique MRS-detectable metabolic profile that can potentially be exploited for early non-invasive, clinically translatable detection of response to emerging IDHmut inhibitors.

Anatomical location differences between mutated and wild-type isocitrate dehydrogenase 1 in low-grade gliomas

2017 ◽  
Vol 127 (10) ◽  
pp. 873-880 ◽  
Author(s):  
Jinhua Yu ◽  
Zhifeng Shi ◽  
Chunhong Ji ◽  
Yuxi Lian ◽  
Yuanyuan Wang ◽  
...  
Keyword(s):  
Isocitrate Dehydrogenase ◽  
Anatomical Location ◽  
Low Grade ◽  
Wild Type ◽  
Isocitrate Dehydrogenase 1 ◽  
Low Grade Gliomas

EXTH-46. MRS BASED BIOMARKERS OF IDH1 MUTANT GLIOMA RESPONSE TO THE IDH INHIBITOR BAY-1436032

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi173-vi173
Author(s):  
Donghyun Hong ◽  
Noriaki Minami ◽  
Céline Taglang ◽  
Georgios Batsios ◽  
Anne Marie Gillespie ◽  
...  
Keyword(s):  
Animal Models ◽  
Animal Studies ◽  
Response To Treatment ◽  
Resonance Spectroscopy ◽  
Low Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
1H Mrs ◽  
Hyperpolarized 13C ◽  
13C Mrs ◽  
Mutant Idh1

Abstract Gliomas are the most prevalent type of brain tumor in the central nervous system. Mutations in the cytosolic enzyme isocitrate dehydrogenase 1 (IDH1) are a common feature of primary low-grade gliomas, catalyzing the conversion of α-ketoglutarate (αKG) to the oncometabolite 2-hydroxyglutarate (2HG), and mutant IDH1 is a therapeutic target for these tumors. Several mutant IDH inhibitors are currently in clinical trials, nonetheless, complementary non-invasive early biomarkers to assess drug delivery and potential therapeutic response are still needed. The goal of this study was therefore to determine the potential of 1H and hyperpolarized 13C magnetic resonance spectroscopy (MRS)-based biomarkers as indicators of mutant IDH1 low-grade glioma response to treatment with the clinically-relevant IDH1 inhibitor BAY-1436032 in cells and animal models. Immortalized human astrocytes engineered to express mutant IDH1 were treated with 500nM (IC50 value) of BAY-1436032 and BT257 tumors implanted in rats were treated with 150mg/kg of BAY-1436032. To assess steady-state metabolite levels, 1H MRS spectra were acquired on a 500 MHz MRS cancer for cells and a 3 T scanner for animal studies. To assess metabolic fluxes, we used hyperpolarized 13C MRS and probed the fate of hyperpolarized [1-13C]αKG. 1H MRS showed a significant decrease in 2HG as well as a significant increase in glutamate (Glu) and phosphocholine (PCh) following BAY-1436032 treatment in both cell and animal models compared to controls. Furthermore, hyperpolarized 13C MRS showed that hyperpolarized 2HG production from hyperpolarized [1-13C]αKG was decreased and hyperpolarized glutamate production from hyperpolarized [1-13C]αKG was increased in the BAY-1436032 treated groups compared to controls. These findings are consistent with our previous study, which investigated the MRS-detectable consequences of two other mutant IDH inhibitors: AG120 and AG881. Collectively, our work identifies translatable MRS-based metabolic biomarkers of mutant IDH1 inhibition.

scholarly journals Computational Analysis of IDH1, IDH2, and TP53 Mutations in Low-Grade Gliomas Including Oligodendrogliomas and Astrocytomas

2020 ◽  
Vol 19 ◽  
pp. 117693512091583 ◽  
Author(s):  
Mohammed Amine Bendahou ◽  
Housna Arrouchi ◽  
Wiame Lakhlili ◽  
Loubna Allam ◽  
Tarik Aanniz ◽  
...  
Keyword(s):  
Isocitrate Dehydrogenase ◽  
Computational Analysis ◽  
Catalytic Site ◽  
Dimensional Structure ◽  
Low Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
Modeling Tools ◽  
Low Grade Gliomas ◽  
Isocitrate Dehydrogenase 2 ◽  
The Impact

Introduction: The emergence of new omics approaches, such as genomic algorithms to identify tumor mutations and molecular modeling tools to predict the three-dimensional structure of proteins, has facilitated the understanding of the dynamic mechanisms involved in the pathogenesis of low-grade gliomas including oligodendrogliomas and astrocytomas. Methods: In this study, we targeted known mutations involved in low-grade gliomas, starting with the sequencing of genomic regions encompassing exon 4 of isocitrate dehydrogenase 1 ( IDH1) and isocitrate dehydrogenase 2 ( IDH2) and the four exons (5-6 and 7-8) of TP53 from 32 samples, followed by computational analysis to study the impact of these mutations on the structure and function of 3 proteins IDH1, IDH2, and p53. Results: We obtain a mutation that has an effect on the catalytic site of the protein IDH1 as R132H and on the catalytic site of the protein IDH2 as R172M. Other mutations at p53 have been identified as K305N, which is a pathogenic mutation; R175 H, which is a benign mutation; and R158G, which disrupts the structural conformation of the tumor suppressor protein. Conclusion: In low-grade gliomas, mutations in IDH1, IDH2, and TP53 may be the key to tumor progression because they have an effect on the function of the protein such as mutations R132H in IDH1 and R172M in IDH2, which change the function of the enzyme alpha-ketoglutarate, or R158G in TP53, which affects the structure of the generated protein, thus their importance in understanding gliomagenesis and for more accurate diagnosis complementary to the anatomical pathology tests.

Monitoring tumour response with proton resonance spectroscopy in low-grade gliomas

2001 ◽  
Vol 51 (3) ◽  
pp. 164
Author(s):  
L. Viviers ◽  
P. Murphy ◽  
J. Britton ◽  
C. Abson ◽  
M. Leach ◽  
...  
Keyword(s):  
Tumour Response ◽  
Resonance Spectroscopy ◽  
Low Grade ◽  
Proton Resonance ◽  
Low Grade Gliomas

scholarly journals Clinical Management of Diffuse Low-Grade Gliomas

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3008
Author(s):  
Giuseppe Lombardi ◽  
Valeria Barresi ◽  
Antonella Castellano ◽  
Emeline Tabouret ◽  
Francesco Pasqualetti ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Targeted Therapy ◽  
Operative Management ◽  
Molecular Profile ◽  
Low Grade ◽  
Low Grade Gliomas ◽  
Therapeutic Modalities ◽  
Molecular Features ◽  
Prognostic Stratification

Diffuse low-grade gliomas (LGG) represent a heterogeneous group of primary brain tumors arising from supporting glial cells and usually affecting young adults. Advances in the knowledge of molecular profile of these tumors, including mutations in the isocitrate dehydrogenase genes, or 1p/19q codeletion, and in neuroradiological techniques have contributed to the diagnosis, prognostic stratification, and follow-up of these tumors. Optimal post-operative management of LGG is still controversial, though radiation therapy and chemotherapy remain the optimal treatments after surgical resection in selected patients. In this review, we report the most important and recent research on clinical and molecular features, new neuroradiological techniques, the different therapeutic modalities, and new opportunities for personalized targeted therapy and supportive care.

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