scholarly journals From genomics to the clinic: biological and translational insights of mutant IDH1/2 in glioma

2013 ◽  
Vol 34 (2) ◽  
pp. E2 ◽  
Author(s):  
Gavin P. Dunn ◽  
Ovidiu C. Andronesi ◽  
Daniel P. Cahill
Keyword(s):  
Hypoxia Inducible Factor ◽  
Diagnostic Tools ◽  
Low Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
Treatment Algorithms ◽  
Recurrent Mutations ◽  
Molecular Landscape ◽  
Mutant Idh1 ◽  
And Function

The characterization of the genomic alterations across all human cancers is changing the way that malignant disease is defined and treated. This paradigm is extending to glioma, where the discovery of recurrent mutations in the isocitrate dehydrogenase 1 (IDH1) gene has shed new light on the molecular landscape in glioma and other IDH-mutant cancers. The IDH1 mutations are present in the vast majority of low-grade gliomas and secondary glioblastomas. Rapidly emerging work on the consequences of mutant IDH1 protein expression suggests that its neomorphic enzymatic activity catalyzing the production of the oncometabolite 2-hydroxyglutarate influences a range of cellular programs that affect the epigenome, transcriptional programs, hypoxia-inducible factor biology, and development. In the brief time since its discovery, knowledge of the IDH mutation status has had significant translational implications, and diagnostic tools are being used to monitor its expression and function. The concept of IDH1-mutant versus IDH1-wild type will become a critical early distinction in diagnostic and treatment algorithms.

scholarly journals Inhibitor potency varies widely among tumor-relevant human isocitrate dehydrogenase 1 mutants

2018 ◽  
Vol 475 (20) ◽  
pp. 3221-3238 ◽  
Author(s):  
Diego Avellaneda Matteo ◽  
Grace A. Wells ◽  
Lucas A. Luna ◽  
Adam J. Grunseth ◽  
Olga Zagnitko ◽  
...  
Keyword(s):  
Isocitrate Dehydrogenase ◽  
Resistance Mutation ◽  
Poor Response ◽  
Fold Increase ◽  
Structural Features ◽  
Low Grade ◽  
Wild Type ◽  
Isocitrate Dehydrogenase 1 ◽  
Dynamics Simulations ◽  
Mutant Idh1

Mutations in isocitrate dehydrogenase 1 (IDH1) drive most low-grade gliomas and secondary glioblastomas and many chondrosarcomas and acute myeloid leukemia cases. Most tumor-relevant IDH1 mutations are deficient in the normal oxidization of isocitrate to α-ketoglutarate (αKG), but gain the neomorphic activity of reducing αKG to D-2-hydroxyglutarate (D2HG), which drives tumorigenesis. We found previously that IDH1 mutants exhibit one of two reactivities: deficient αKG and moderate D2HG production (including commonly observed R132H and R132C) or moderate αKG and high D2HG production (R132Q). Here, we identify a third type of reactivity, deficient αKG and high D2HG production (R132L). We show that R132Q IDH1 has unique structural features and distinct reactivities towards mutant IDH1 inhibitors. Biochemical and cell-based assays demonstrate that while most tumor-relevant mutations were effectively inhibited by mutant IDH1 inhibitors, R132Q IDH1 had up to a 16 300-fold increase in IC50 versus R132H IDH1. Only compounds that inhibited wild-type (WT) IDH1 were effective against R132Q. This suggests that patients with a R132Q mutation may have a poor response to mutant IDH1 therapies. Molecular dynamics simulations revealed that near the NADP+/NADPH-binding site in R132Q IDH1, a pair of α-helices switches between conformations that are more wild-type-like or more mutant-like, highlighting mechanisms for preserved WT activity. Dihedral angle changes in the dimer interface and buried surface area charges highlight possible mechanisms for loss of inhibitor affinity against R132Q. This work provides a platform for predicting a patient's therapeutic response and identifies a potential resistance mutation that may arise upon treatment with mutant IDH inhibitors.

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 RDNA-06. TARGETING IDH1/2-MUTANT GLIOMAS WITH UNIQUE COMBINATIONS OF DNA REPAIR INHIBITORS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi208-vi208
Author(s):  
Amrita Sule ◽  
Ranjit Bindra
Keyword(s):  
Clinical Trials ◽  
Dna Repair ◽  
Myeloid Leukemia ◽  
Parp Inhibitors ◽  
Low Grade ◽  
High Fidelity ◽  
Isocitrate Dehydrogenase 1 ◽  
Dna Repair Inhibitors ◽  
Mutant Idh1 ◽  
Tumor Types

Abstract Mutations in the Isocitrate Dehydrogenase-1 and -2 (IDH1/2) genes occur in the vast majority of low-grade and secondary high-grade gliomas. These neomorphic mutations occur early on in gliomagenesis leading to the production of 2-Hydroxyglutarate (2HG). 2HG has been implicated in tumorigenesis via inhibiting α-ketoglutarate (αKG)-dependent dioxygenases. Our group recently demonstrated that the production of 2HG suppresses the high-fidelity homologous recombination (HR) DNA repair pathway, resulting in a state of “BRCAness”. We initially found that mutant IDH1/2-induced BRCAness confers exquisite sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors, a finding which now has been replicated by multiple independent laboratories. Although IDH1/2 mutations were first identified in gliomas and acute myeloid leukemia (AML) cells, multiple other tumor types have subsequently been shown to harbor these mutations. Current clinical trials are testing the efficacy of PARP inhibitors as a monotherapy, as well as in combination with other DNA repair inhibitors. Here, we demonstrate that novel combinations of DNA repair inhibitors can be utilized to synergistically target IDH1/2-mutant glioma cells. In particular, we demonstrate potent synergy with ATRi and PARPis, a finding which was validated in multiple structurally unique drugs within these classes. As this combination is active in BRCA1/2-mutant cancers, in particular after the emergence of PARPi resistance, these data suggest are consistent with an underlying HR defect in IDH1/2-mutant gliomas. These preclinical investigations will provide a blueprint for future clinical trials combining PARP and ATR inhibitors in the treatment of glioblastoma.

Vorasidenib (VOR; AG-881), an inhibitor of mutant IDH1 and IDH2, in patients (pts) with recurrent/progressive glioma: Updated results from the phase I non-enhancing glioma population.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2504-2504 ◽  
Author(s):  
Ingo K. Mellinghoff ◽  
Katherine B. Peters ◽  
Timothy Francis Cloughesy ◽  
Howard A. Burris III ◽  
Elizabeth Anne Maher ◽  
...  
Keyword(s):  
Phase 1 ◽  
Objective Response ◽  
Low Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
Eligibility Criteria ◽  
Dual Inhibitor ◽  
Study Results ◽  
Grade 3 ◽  
Mutant Idh1 ◽  
Favorable Safety

2504 Background: Isocitrate dehydrogenase 1 and 2 mutations (m IDH1/2) occur in approximately 70% and 4% of low-grade gliomas (LGGs), respectively, promoting oncogenesis via increased production of D-2-hydroxyglutarate. In this ongoing phase 1 trial, VOR, a potent, oral, reversible, brain-penetrant, first-in-class dual inhibitor of mIDH1/2, is being evaluated in advanced m IDH1/2 solid tumors, including gliomas. Safety and preliminary results were presented previously (Mellinghoff et al., J Clin Oncol 2018). Here, we report updated data for the non-enhancing glioma pt population. Methods: Pts with recurrent/progressive m IDH1/2 glioma received VOR daily (continuous 28-day cycles). Key eligibility criteria included: ≥18 years; histologically or cytologically confirmed glioma with documented m IDH1/2; ECOG 0-2; and evaluable disease by RANO-LGG criteria. Dose escalation cohorts enrolled using a Bayesian logistic regression model (BLRM) escalation guided by the overdose control (EWOC). Tumor response was evaluated by MRI every 8 weeks using RANO-LGG criteria by local assessment. Results: As of 28 Nov 2019, 22 pts with non-enhancing glioma had received VOR and 8 (36%) remain on treatment. M/F, 8/14; grade 2/3, 17/5; median age, 47 years; m IDH1/2, 20/1; 1p19q intact, 9/22; median (range) number of prior systemic therapies, 2 (1–4). Common (≥5 pts) treatment-emergent adverse events (AEs) of any grade and regardless of causality included increased ALT/AST (63.6%/59.1%), headache (45.5%), nausea (40.9%), neutropenia (31.8%), fatigue and hyperglycemia (27.3% each), and seizures and decreased white blood cell count (22.7% each). Transaminase elevations were grade 1 in severity at dose levels < 100mg and were less frequent (5 [38.5%] of 13 pts). Three subjects had related grade ≥3 AEs; 2 discontinued due to AEs. Objective response rate was 13.6% (1 partial response, 2 minor responses), and 17 (77.3%) pts achieved stable disease. 60.5% of pts were progression free and alive at 24 months. Conclusions: In this previously treated population with non-enhancing glioma, VOR was associated with a favorable safety profile. The study results also show encouraging preliminary activity within that population, with PFS duration extending to 24 months or longer in 60% of participants. A global randomized phase 3 study of VOR in grade 2 non-enhancing glioma pts who have had surgery only is currently enrolling (NCT04164901). Clinical trial information: NCT02481154 .

scholarly journals Gene of the month: IDH1

2020 ◽  
Vol 73 (10) ◽  
pp. 611-615
Author(s):  
Cassandra Bruce-Brand ◽  
Dhirendra Govender
Keyword(s):  
Somatic Mutations ◽  
Oxidative Decarboxylation ◽  
Low Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
Maffucci Syndrome ◽  
Downstream Effects ◽  
Diffuse Gliomas ◽  
Ollier Disease ◽  
Mutant Idh1 ◽  
Acute Myeloid

Isocitrate dehydrogenase 1 (IDH1) encodes a protein which catalyses the oxidative decarboxylation of isocitrate to α-ketoglutarate. Mutant IDH1 favours the production of 2-hydroxyglutarate, an oncometabolite with multiple downstream effects which promote tumourigenesis. IDH1 mutations have been described in a number of neoplasms most notably low-grade diffuse gliomas, conventional central and periosteal cartilaginous tumours and cytogenetically normal acute myeloid leukaemia. Post zygotic somatic mutations of IDH1 characterise the majority of cases of Ollier disease and Maffucci syndrome. IDH1 mutations are uncommon in epithelial neoplasia but have been described in cholangiocarcinoma.

scholarly journals Immune Profiling of Gliomas Reveals a Connection with IDH1/2 Mutations, Tau Function and the Vascular Phenotype

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3230
Author(s):  
Teresa Cejalvo ◽  
Ricardo Gargini ◽  
Berta Segura-Collar ◽  
Pablo Mata-Martínez ◽  
Beatriz Herranz ◽  
...  
Keyword(s):  
Immune Cells ◽  
Checkpoint Inhibitors ◽  
Genetic Profile ◽  
Wild Type ◽  
Isocitrate Dehydrogenase 1 ◽  
Vascular Phenotype ◽  
Tumor Immune Microenvironment ◽  
Important Challenge ◽  
Mutant Idh1

Background: Gliomas remain refractory to all attempted treatments, including those using immune checkpoint inhibitors. The characterization of the tumor (immune) microenvironment has been recognized as an important challenge to explain this lack of response and to improve the therapy of glial tumors. Methods: We designed a prospective analysis of the immune cells of gliomas by flow cytometry. Tumors with or without isocitrate dehydrogenase 1/2 (IDH1/2) mutations were included in the study. The genetic profile and the presence of different molecular and cellular features of the gliomas were analyzed in parallel. The findings were validated in syngeneic mouse models. Results: We observed that few immune cells infiltrate mutant IDH1/2 gliomas whereas the immune content of IDH1/2 wild-type tumors was more heterogeneous. Some of them contained an important immune infiltrate, particularly enriched in myeloid cells with immunosuppressive features, but others were more similar to mutant IDH1/2 gliomas, with few immune cells and a less immunosuppressive profile. Notably, we observed a direct correlation between the percentage of leukocytes and the presence of vascular alterations, which were associated with a reduced expression of Tau, a microtubule-binding protein that controls the formation of tumor vessels in gliomas. Furthermore, overexpression of Tau was able to reduce the immune content in orthotopic allografts of GL261 cells, delaying tumor growth. Conclusions: We have confirmed the reduced infiltration of immune cells in IDH1/2 mutant gliomas. By contrast, in IDH1/2 wild-type gliomas, we have found a direct correlation between the presence of vascular alterations and the entrance of leukocytes into the tumors. Interestingly, high levels of Tau inversely correlated with the vascular and the immune content of gliomas. Altogether, our results could be exploited for the design of more successful clinical trials with immunomodulatory molecules.

scholarly journals Immunohistochemical and Molecular Characterization of Endometrial Stromal Sarcomas

2020 ◽  
Vol 13 ◽  
pp. 2632010X2091673
Author(s):  
Sneha Subbaraya ◽  
Sudha S Murthy ◽  
Sandhya Devi G
Keyword(s):  
Cyclin D1 ◽  
Molecular Characterization ◽  
Oestrogen Receptor ◽  
Gene Rearrangement ◽  
Uterine Sarcoma ◽  
World Health ◽  
Diagnostic Tools ◽  
Low Grade ◽  
Rare Tumours

Introduction: Endometrial stromal sarcomas (ESSs) are rare and characterized by translocations t(7;17)(p15;q11.2) and t(10;17)(q22;p13), resulting in JAZF1-SUZ12 and YWHAE-FAM22 gene fusions used for defining low-grade (LG-ESS) and high-grade (HG-ESS) tumours. Aim: The objective of the study was to characterize ESSs using immunohistochemical and molecular markers. Material and Methods: Patients diagnosed as having ESSs between January 2014 and December 2018 were included in the study. The slides were reviewed along with a panel of immunohistochemical markers, CD10, cyclin D1, oestrogen receptor (ER) and progesterone receptor (PR), Ki67, and vimentin and classified according to World Health Organization (2014) criteria into LG-ESS, HG-ESS, and undifferentiated uterine sarcoma (UUS). Molecular characterization was performed by fluorescence in situ hybridization using relevant probes. Results: Over a 4-year period, 552 cases of endometrial malignancies were reported, 10 of which were ESS (1.8%). Of these, 5 were LG-ESS, 3 HG-ESS, and 2 UUS. CD10 was 100% sensitive and 75% specific for LG-ESS. Oestrogen receptor and PR were 100% specific but less sensitive (80%) for LG-ESS. Forty per cent (2/5) of LG-ESS demonstrated JAZF1-SUZ12 gene rearrangement. All 3 cases of HG-ESS showed diffuse strong cyclin D1 (>70% nuclei) positivity and were negative for cluster differentiation 10, ER, and PR and demonstrated YWHAE gene rearrangement. None of the UUS cases demonstrated this gene rearrangement. Conclusion: Endometrial stromal sarcomas are rare tumours (1.8% in this study). JAZF1-SUZ12 and YWHAE-FAM22 gene rearrangement helps in accurate characterization of ESS and can be used as diagnostic tools especially when the diagnosis is unclear or difficult. Cyclin D1 can be used as an adjuvant immunomarker for YWHAE gene–rearranged HG-ESS.

Functional characterization of human brown adipose tissue metabolism

2020 ◽  
Vol 477 (7) ◽  
pp. 1261-1286 ◽  
Author(s):  
Marie Anne Richard ◽  
Hannah Pallubinsky ◽  
Denis P. Blondin
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Functional Characterization ◽  
Human Infants ◽  
Positron Emission ◽  
Brown Adipose ◽  
Treatment Of Obesity ◽  
And Function

Brown adipose tissue (BAT) has long been described according to its histological features as a multilocular, lipid-containing tissue, light brown in color, that is also responsive to the cold and found especially in hibernating mammals and human infants. Its presence in both hibernators and human infants, combined with its function as a heat-generating organ, raised many questions about its role in humans. Early characterizations of the tissue in humans focused on its progressive atrophy with age and its apparent importance for cold-exposed workers. However, the use of positron emission tomography (PET) with the glucose tracer [18F]fluorodeoxyglucose ([18F]FDG) made it possible to begin characterizing the possible function of BAT in adult humans, and whether it could play a role in the prevention or treatment of obesity and type 2 diabetes (T2D). This review focuses on the in vivo functional characterization of human BAT, the methodological approaches applied to examine these features and addresses critical gaps that remain in moving the field forward. Specifically, we describe the anatomical and biomolecular features of human BAT, the modalities and applications of non-invasive tools such as PET and magnetic resonance imaging coupled with spectroscopy (MRI/MRS) to study BAT morphology and function in vivo, and finally describe the functional characteristics of human BAT that have only been possible through the development and application of such tools.

Parasite defense mechanisms in bees: behavior, immunity, antimicrobials, and symbionts

2019 ◽  
Vol 4 (1) ◽  
pp. 59-76 ◽  
Author(s):  
Alison E. Fowler ◽  
Rebecca E. Irwin ◽  
Lynn S. Adler
Keyword(s):  
Defense Mechanisms ◽  
Poor Quality ◽  
Future Research ◽  
Immune Priming ◽  
Social Bees ◽  
Bee Health ◽  
Landscape Scales ◽  
And Function ◽  
Solitary Species

Parasites are linked to the decline of some bee populations; thus, understanding defense mechanisms has important implications for bee health. Recent advances have improved our understanding of factors mediating bee health ranging from molecular to landscape scales, but often as disparate literatures. Here, we bring together these fields and summarize our current understanding of bee defense mechanisms including immunity, immunization, and transgenerational immune priming in social and solitary species. Additionally, the characterization of microbial diversity and function in some bee taxa has shed light on the importance of microbes for bee health, but we lack information that links microbial communities to parasite infection in most bee species. Studies are beginning to identify how bee defense mechanisms are affected by stressors such as poor-quality diets and pesticides, but further research on this topic is needed. We discuss how integrating research on host traits, microbial partners, and nutrition, as well as improving our knowledge base on wild and semi-social bees, will help inform future research, conservation efforts, and management.

Comparison of Immunological and Functional Assays for Measurement of Soluble Fibrin

1995 ◽  
Vol 74 (02) ◽  
pp. 673-679 ◽  
Author(s):  
C E Dempfle ◽  
S A Pfitzner ◽  
M Dollman ◽  
K Huck ◽  
G Stehle ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Low Grade ◽  
Plasma Samples ◽  
Normal Range ◽  
Soluble Fibrin ◽  
Discriminating Power ◽  
Fibrin Monomer ◽  
Cerebral Ischemic

SummaryVarious assays have been developed for quantitation of soluble fibrin or fibrin monomer in clinical plasma samples, since this parameter directly reflects in vivo thrombin action on fibrinogen. Using plasma samples from healthy blood donors, patients with cerebral ischemic insult, patients with septicemia, and patients with venous thrombosis, we compared two immunologic tests using monoclonal antibodies against fibrin-specific neo-epitopes, and two functional tests based on the cofactor activity of soluble fibrin complexes in tPA-induced plasminogen activation. Test A (Enzymun®-Test FM) showed the best discriminating power among normal range and pathological samples. Test B (Fibrinostika® soluble fibrin) clearly separated normal range from pathological samples, but failed to discriminate among samples from patients with low grade coagulation activation in septicemia, and massive activation in venous thrombosis. Functional test C (Fibrin monomer test Behring) displayed good discriminating power between normal and pathological range samples, and correlated with test A (r = 0.61), whereas assay D (Coa-Set® Fibrin monomer) showed little discriminating power at values below 10 μg/ml and little correlation with other assays. Standardization of assays will require further characterization of analytes detected.

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