scholarly journals The Distribution and Significance of IDH Mutations in Gliomas

10.5772/52357 ◽  
2013 ◽  
Author(s):  
Marta Mellai ◽  
Valentina Caldera ◽  
Laura Annovazzi ◽  
Davide Schiffer
Keyword(s):  
Idh Mutations

Targeting IDH Mutations in AML: Wielding the Double-edged Sword of Differentiation

2020 ◽  
Vol 20 (7) ◽  
pp. 490-500 ◽  
Author(s):  
Justin S. Becker ◽  
Amir T. Fathi
Keyword(s):  
Genome Structure ◽  
Cellular Metabolism ◽  
Standard Of Care ◽  
Competitive Inhibitor ◽  
Driver Mutations ◽  
New Class ◽  
Regulatory Enzymes ◽  
Idh Mutations ◽  
Genomic Characterization

The genomic characterization of acute myeloid leukemia (AML) by DNA sequencing has illuminated subclasses of the disease, with distinct driver mutations, that might be responsive to targeted therapies. Approximately 15-23% of AML genomes harbor mutations in one of two isoforms of isocitrate dehydrogenase (IDH1 or IDH2). These enzymes are constitutive mediators of basic cellular metabolism, but their mutated forms in cancer synthesize an abnormal metabolite, 2- hydroxyglutarate, that in turn acts as a competitive inhibitor of multiple gene regulatory enzymes. As a result, leukemic IDH mutations cause changes in genome structure and gene activity, culminating in an arrest of normal myeloid differentiation. These discoveries have motivated the development of a new class of selective small molecules with the ability to inhibit the mutant IDH enzymes while sparing normal cellular metabolism. These agents have shown promising anti-leukemic activity in animal models and early clinical trials, and are now entering Phase 3 study. This review will focus on the growing preclinical and clinical data evaluating IDH inhibitors for the treatment of IDH-mutated AML. These data suggest that inducing cellular differentiation is central to the mechanism of clinical efficacy for IDH inhibitors, while also mediating toxicity for patients who experience IDH Differentiation Syndrome. Ongoing trials are studying the efficacy of IDH inhibitors in combination with other AML therapies, both to evaluate potential synergistic combinations as well as to identify the appropriate place for IDH inhibitors within existing standard-of-care regimens.

scholarly journals B2M overexpression correlates with malignancy and immune signatures in human gliomas

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hao Zhang ◽  
Biqi Cui ◽  
Yulai Zhou ◽  
Xinxing Wang ◽  
Wantao Wu ◽  
...  
Keyword(s):  
Critical Role ◽  
Cell Types ◽  
Potential Candidate ◽  
Egfr Amplification ◽  
Immune Signatures ◽  
Idh Mutations ◽  
Pten Deletion ◽  
R Project ◽  
Patient Prognosis ◽  
Worse Prognosis

AbstractBecause of the limited treatment strategy of gliomas, the key of diagnosis and treatment is finding new molecular biomarkers. Here, we explored the potential of β2-microglobulin (B2M) to serve as a hopeful candidate for immunotherapy or diagnostic biomarker in gliomas. The genomic profiles, clinical characteristics, and immune signatures were analyzed based on TCGA and CGGA databases. We carried out the whole statistical analyses using R project. High B2M expression correlated with worse prognosis. Somatic mutations of gliomas with high B2M expression are associated with PTEN deletion and EGFR amplification. Isocitrate dehydrogenase (IDH) mutations accounted for 82% in gliomas with low B2M expression. In addition, B2M positively correlated with ESTIMATE scores, interacted with infiltrating immune and stromal cell types. B2M also suppressed anti-tumor immunity through immune related processes. Meanwhile, B2M was associated with immune checkpoint molecules and inflammatory activities. Finally, functional annotation of the identified B2M related genes verified that B2M was a potential candidate for immunotherapy. We confirmed that B2M played a critical role in tumor progression, patient prognosis and immunotherapy of gliomas.

scholarly journals EG-08 * IDH MUTATIONS IN GLIOMAS ASSOCIATED WITH ENCHONDROMATOSIS

2014 ◽  
Vol 16 (suppl 5) ◽  
pp. v76-v76
Author(s):  
M. K. Nicholas ◽  
L. Joseph ◽  
S. Venneti ◽  
A. Daher ◽  
P. Pytel
Keyword(s):  
Idh Mutations

16. Physiological effects of IDH1 loss-of-function on Chondrocyte Differentiation through Hedgehog Pathway upregulation

2018 ◽  
Author(s):  
Cassie Tyson
Keyword(s):  
Developmental Stages ◽  
Hedgehog Pathway ◽  
Chondrocyte Differentiation ◽  
Loss Of Function ◽  
Wild Type ◽  
Phenotypic Analysis ◽  
Growth Plate Chondrocytes ◽  
Idh Mutations ◽  
Cartilage Tumors ◽  
Deficient Mice

Cartilage tumors are the most common and terminal primary neoplasms in bone. Physiologically, bones formed through endochondral ossification are regulated by the Hedgehog pathway and Parathyroid hormone-like hormone feedback loop. The upregulation of the infamous Hedgehog pathway has been demonstrated in several non-cartilaginous neoplasms. Recently, frequent mutational events of isocitrate dehydrogenase1 (IDH1) were identified in cartilage tumors. In other neoplasms, IDH mutations produces an oncometabolite that can promote HIF1a activation, contributing to tumorigenesis. Currently, the role of IDH1 mutations in cartilage tumors remain unknown. Investigating the physiological aspect of IDH1proves useful in identifying novel therapeutic targets for cartilage tumors. IDH1 deficient and wild-type littermates, were harvested for forelimbs and hindlimbs at various developmental stages for phenotypic analysis via hematoxylin and eosin staining. Histological analysis demonstrated IDH1 homozygous deficient mice at embryonic stages exhibited dwarfism and an elongated layer of hypertrophic chondrocytes. This was verified via immunohistochemistry Type 10 Collagen staining and Quantitative PCR (qPCR) using the chondrocyte terminal differentiation marker Col10a1. Whole skeletons of IDH1 deficient mice were subjected to skeletal double staining which demonstrated delayed mineralization of underdeveloped IDH1 deficient mice contrasted with wild-type littermates. qPCR was performed to examine the status of chondrocyte differentiation through the Hedgehog pathway in cultured primarymouse growth plate chondrocytes. Interestingly, IDH1 deficient non-neoplastic cells revealed significant upregulation of Hedgehog target molecules in IDH1 deficient chondrocytes. As a result, the loss-offunction of IDH1 was identified as a potential impairment of chondrocyte differentiation and a factor towards chondrocyte tumorgenisis.

A multicenter open-label phase 1 study evaluating the safety and tolerability of HMPL-306 in patients with locally advanced or metastatic solid tumors with IDH mutations.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3159-TPS3159
Author(s):  
Filip Janku ◽  
John S. Kauh ◽  
Christopher Tucci ◽  
Zhao Yang ◽  
Marek K. Kania ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Tricarboxylic Acid Cycle ◽  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Low Grade Glioma ◽  
Statistical Hypothesis ◽  
Low Grade ◽  
Open Label ◽  
Idh Mutations

TPS3159 Background: Isocitrate dehydrogenase (IDH) is a rate-limiting tricarboxylic acid cycle enzyme with 3 isoforms. Mutations in IDH1 and IDH2 result in gain-of-function activity that can cause tumor formation and/or progression and have been associated with various tumor types. Therefore, selective, single mutant IDH (mIDH) isotype inhibitors (mIDH1 or mIDH2) can lead to insufficient efficacy and the potential for tumor resistance. HMPL-306 is an innovative, small-molecule, orally available, highly selective, potent inhibitor of both mIDH1 and mIDH2. Clinical development of a compound that concurrently targets, inhibits, and suppresses multiple mIDHs could lead to significant and durable clinical benefit for patients (pts) with solid tumors harboring IDH mutations. Methods: This is a phase 1, open-label, dose escalation (Part 1) and dose expansion (Part 2) study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of HMPL-306 in pts ≥18 years with locally advanced or metastatic solid tumors with any IDH mutations. HMPL-306 will be administered orally, once daily in a 28-day continuous dosing treatment cycle. The HMPL-306 dose will be escalated in Part 1 according to the modified toxicity probability interval-2 (mTPI-2) design in 4 cohorts in approximately 15-20 pts: 50, 100, 150, and 200 mg. Eligible pts must have locally advanced or metastatic solid tumors with IDH1 or IDH2 mutations. The primary objectives are to evaluate safety, dose limiting toxicities (DLTs), tolerability, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and PK. Approximately 95 pts will be enrolled at the RP2D in Part 2 to further characterize the safety, tolerability, PK, PD, and preliminary anti-tumor activities of HMPL-306. Part 2 will include 5 dose expansion cohorts: cholangiocarcinoma (n = 20), skeletal chondrosarcoma (n = 20), low-grade glioma (n = 20), perioperative low-grade glioma (n = 15), any other solid tumor harboring an IDH1/2 mutation (n = 20). All pts will continue treatment until disease progression, unacceptable toxicity, withdrawal of consent, or at the investigator’s discretion. Safety will be assessed based on reports of adverse events including clinical laboratory testing, vital signs, physical examinations, and electrocardiograms. All pts who receive any study treatment will be included in safety and efficacy analyses. Antitumor activity based on investigator-assessed overall response will be evaluated using descriptive analyses. Objective response rate will be calculated with 95% confidence interval using the Clopper-Pearson method. The Kaplan-Meier method will be used to summarize the time-to-event data such as progression-free survival and duration of response. No statistical hypothesis testing is planned. Enrollment started February 2021.

IMMU-04. UNVEILING THE TUMOR-METABOLOME-IMMUNITY AXIS OF GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi92-vi92
Author(s):  
Mirco Friedrich ◽  
Lukas Bunse ◽  
Roman Sankowski ◽  
Wolfgang Wick ◽  
Marco Prinz ◽  
...  
Keyword(s):  
T Cell ◽  
Single Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Myeloid Cell ◽  
Tumor Evolution ◽  
Large Neutral Amino Acid ◽  
Immune Microenvironment ◽  
Idh Mutations

Abstract The glioma microenvironment orchestrates tumor evolution, progression, and resistance to therapy. In high-grade gliomas, microglia and monocyte-derived macrophages constitute up to 70% of the tumor mass. However, the dynamics and phenotypes of intratumoral myeloid cells during tumor progression are poorly understood. Here we define myeloid cellular states in gliomas by longitudinal single-cell profiling and demonstrate their strict control by the tumor genotype. We report the unexpected and clinically highly relevant finding that human as well as murine gliomas with Isocitrate Dehydrogenase (IDH)1-R132H, a key oncogenic driver mutation of glioma, subdue their innate immune microenvironment by prompting a multifaceted reprogramming of myeloid and T cell metabolism. We employed integrated single-cell transcriptomic, time-of-flight mass cytometry and proteomic analyses of human healthy cortex control and glioma samples to identify myeloid cell subsets with distinct fates in IDH-mutated glioma that diverge from canonical trajectories of antigen-presenting cells as a result of a monocyte-to-macrophage differentiation block. Moving beyond single time point assessments, we now longitudinally describe differential immune cell infiltration and phenotype dynamics during glioma progression that are orchestrated by a fluctuating network of resident microglial cells and educated recruited immune cells. IDH mutations in glioma induce a tolerogenic alignment of their immune microenvironment through increased tryptophan uptake via large neutral amino acid transporter (LAT1)-CD98 and subsequent activation of the aryl hydrocarbon receptor (AHR) in educated blood-borne macrophages. In experimental tumor models, this immunosuppressive phenotype was reverted by LAT1-CD98 and AHR inhibitors. Taken together with direct effects on T cell activation, our findings not only link this oncogenic metabolic pathway to distinct immunosuppressive pathways but also provide the rationale and novel molecular targets for the development of immunotherapeutic concepts addressing the disease-defining microenvironmental effects of IDH mutations.

Intraoperative Assessment of IDH Mutation Status and Tumor Invasioni in Glioma

2021 ◽  
Vol 156 (Supplement_1) ◽  
pp. S141-S142
Author(s):  
H Brown ◽  
R Chen ◽  
R Cooks ◽  
D Garcia ◽  
K Chaichana ◽  
...  
Keyword(s):  
Unmet Need ◽  
Lipid Profiles ◽  
Ionization Mass ◽  
Idh Mutation ◽  
Fresh Tissue ◽  
Mutation Status ◽  
Ms Analysis ◽  
Idh Mutations ◽  
Desi Ms ◽  
Sensitivity Specificity

Abstract Introduction/Objective Maximizing surgical resection in gliomas, while avoiding compromising non-infiltrated tissue, is associated with survival benefit. Current methodologies are suboptimal in providing rapid, intraoperative molecular characterization of tissue. We address this unmet need by using desorption electrospray ionization mass spectrometry (DESI-MS) for the intraoperative molecular assessment of gliomas. Methods/Case Report This prospective study uses intraoperative DESI-MS analysis of fresh tissue to evaluate IDH mutations via 2-hydroxyglutarate intensity and TCP via measurement of N-acetylaspartic acid (NAA) intensity and characteristic lipid profiles in less than three minutes. Blinded review of the tissue smears by a neuropathologist is used to validate IDH mutation status and TCP estimates. Results (if a Case Study enter NA) Presently, 529 biopsies from 85 enrolled patients have been collected and analyzed at two institutions. TCP assessment based on NAA intensity in 203 biopsies at the first institution yielded sensitivity, specificity, and accuracy values of 91, 76, and 83%, whereas TCP estimates via characteristic lipid profiles yielded 76, 85, and 81%, respectively. Assessment of IDH mutation status of 71 core biopsies yielded sensitivity, specificity, and accuracy values of 89, 100, and 94%. Ongoing validation of the methodology is being performed at a second institution, where we have collected 282 biopsies from 36 patients. IDH mutation assessment of the first 15 patients indicate 100% sensitivity, specificity, and accuracy. Conclusion This study represents the first and largest study using DESI-MS for the intraoperative evaluation of IDH status and TCP measurement in gliomas. Prospectively, we propose to modify our DESI-MS system to allow estimation of IDH mutation status and TCP in surgical cavities without the need for a biopsy by placing a surgical material along the margin and transferring material from the blot to a microscope slide prior to DESI-MS analysis. We envision molecular analysis by DESI-MS as a complementary technique to histopathology capable of providing additional clinical information in near real-time.

Prognostic impact of IDH mutations in chondrosarcoma

2021 ◽  
Author(s):  
Makoto Nakagawa ◽  
Masaya Sekimizu ◽  
Makoto Endo ◽  
Eisuke Kobayashi ◽  
Shintaro Iwata ◽  
...  
Keyword(s):  
Prognostic Impact ◽  
Idh Mutations
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