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    BIOMARKER:

    IDH2 R140Q

    i
    Other names: IDH2, Isocitrate Dehydrogenase (NADP(+)) 2, Isocitrate Dehydrogenase (NADP(+)) 2, Mitochondrial, Isocitrate Dehydrogenase 2 (NADP+), Mitochondrial, Isocitrate Dehydrogenase [NADP], Mitochondrial, Oxalosuccinate Decarboxylase, NADP(+)-Specific ICDH, ICD-M, IDH, IDP, MNADP-IDH, D2HGA2, IDHM, IDPM
    Entrez ID:
    3418
    Related biomarkers:
    Expression
    Mutation
    Others
    Related tests:
    17d
    The Validation of Digital PCR-based Minimal Residual Disease (MRD) Detection for the Common Mutations in IDH1 and IDH2 genes in Patients with Acute Myeloid Leukemia. (PubMed, J Mol Diagn)
    Controls and acceptable ranges were also established for each mutation during validation. This study suggests that the QuantStudio 3D Digital PCR assay is a quantitative, sensitive, and reproducible platform for monitoring MRD in AML patients.
    Journal • Minimal residual disease
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH1 mutation • IDH2 mutation • IDH2 R140Q
    1m
    IDH1/2 Mutations in Lung Cancer: A Closer Look at Their Incidence, Origin, and Clinical Characteristics (AMP 2024)
    IDH1/2 mutations are identified in a small subset of NSCLCs. Our findings suggest that >25% of these mutations are hematopoietic in origin with important implications for diagnosis and management of these patients. Among those with mutations arising from the lung neoplasm, IDH1/2 mutations were primarily seen in conjunction with another driver and were subclonal in nature, suggesting patterns of clonal heterogeneity and evolution.
    Clinical • Tumor mutational burden
    |
    EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TMB (Tumor Mutational Burden) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    KRAS mutation • BRAF mutation • IDH wild-type • IDH1 R132 • IDH2 R140Q • IDH1 R132L • IDH2 R140 • IDH2 R172
    |
    MSK-IMPACT
    1m
    Evaluation of Performance of the Idylla IDH1/2 Mutation Assay Using Direct Whole Blood and Bone Marrow (AMP 2024)
    These mutations are targetable using agents such as ivosidenib and vorasedinib in AML... The Biocartis Idylla IDH1-2 mutation assay shows good concordance with ddPCR and an LOD of 2.5% VAF. Though the analytical sensitivity of this assay is lower than ddPCR, this may not be a limitation in acute, newly diagnosed patients presenting with increased blast counts. This assay offers the advantage of direct specimen testing for PB and BM without DNA extraction with faster turnaround time than other methods.
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH1 mutation • IDH2 mutation • IDH1 R132H • IDH2 R172K • IDH1 R132C • IDH1 R132 • IDH2 R140Q • IDH2 R140 • IDH2 R172
    |
    Idylla™ IDH1-2 Mutation Assay
    |
    Tibsovo (ivosidenib)
    1m
    Performance Assessment and Clinical Validation of the Idylla IDH1-2 Mutation Assay Kit in Rapid Detection of IDH Mutations in Acute Myeloid Leukemia (AMP 2024)
    The Idylla IDH1-2 Mutation Assay Kit performed on the Biocartis Idylla system demonstrated a rapid and cost-effective alternative to the standard approaches. This assay can be used to evaluate clinically relevant IDH variants in a much shorter turnaround time and from limited biological samples, which makes this a preferred technique to develop clinical tests for diagnosis, prognosis, and evaluation of treatment in AML.
    Clinical
    |
    KIT (KIT proto-oncogene, receptor tyrosine kinase) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH1 mutation • KIT mutation • IDH1 R132H • IDH2 R172K • IDH1 R132C • IDH1 R132 • IDH1 R132G • IDH2 R140Q • IDH2 R172
    |
    Idylla™ IDH1-2 Mutation Assay
    1m
    NCI-2019-03057: Using the Anticancer Drug Olaparib to Treat Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome With an Isocitrate Dehydrogenase (IDH) Mutation (clinicaltrials.gov)
    P2, N=14, Active, not recruiting, National Cancer Institute (NCI) | N=94 --> 14 | Trial completion date: Dec 2024 --> Nov 2025 | Trial primary completion date: Dec 2024 --> Jan 2024
    Enrollment change • Trial completion date • Trial primary completion date
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH2 mutation • IDH1 R132H • IDH2 R172K • IDH1 R132C • IDH wild-type • IDH1 R132 • IDH1 R132G • IDH2 R140Q • IDH1 R132L • IDH1 R132S • IDH1 R132V • IDH2 R172 • IDH2 R172G
    |
    Lynparza (olaparib)
    2ms
    AML-VAC-XS15-01: protocol of a first-in-human clinical trial to evaluate the safety, tolerability and preliminary efficacy of a multi-peptide vaccine based on leukemia stem cell antigens in acute myeloid leukemia patients. (PubMed, Front Oncol)
    The AML-VAC-XS15-01 study was approved by the Ethics Committee of the Bavarian State medical association and the Paul-Ehrlich Institut (P01392). Clinical trial results will be published in peer-reviewed journals.
    P1 data • Journal • IO biomarker
    |
    IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1)
    |
    IDH2 mutation • NPM1 mutation • IDH2 R140Q
    2ms
    Olaparib in Treating Patients With Advanced Glioma, Cholangiocarcinoma, or Solid Tumors With IDH1 or IDH2 Mutations (clinicaltrials.gov)
    P2, N=145, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2024 --> Jul 2025 | Trial primary completion date: Jul 2024 --> Jul 2025
    Trial completion date • Trial primary completion date • Metastases
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH2 mutation • IDH1 R132H • IDH2 R172K • IDH1 R132C • IDH1 R132 • IDH1 R132G • IDH2 R140Q • IDH1 R132L • IDH1 R132S • IDH1 R132V • IDH2 R172 • IDH2 R172G
    |
    Lynparza (olaparib)
    10ms
    The Idyllaâ„¢ IDH1-2 Mutation Assay Kit: A tool for mutation detection in IDH1 and IDH2 genes (AACR 2024)
    With advancements in molecular diagnostics and precision therapy, IDH inhibitors such as ivosidenib, vorasidenib and enasidenib are now mainstay in management of patients with a susceptible mutation. The Idyllaâ„¢ IDH1-2 Mutation Assay Kit (RUO) is a fully automated qPCR assay for the qualitative detection of 15 common mutations in IDH1 (R132C/H/G/S/L) and IDH2 (R140Q/L/G/W, R172K/M/G/W/S) at codon level. The Idyllaâ„¢ IDH1-2 Mutation Assay Kit demonstrates a high concordance with established reference methods across a range of different specimen types.
    KIT (KIT proto-oncogene, receptor tyrosine kinase) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH1 mutation • IDH2 mutation • KIT mutation • IDH2 R172K • IDH1 R132C • IDH1 R132 • IDH2 R140Q • IDH2 R140 • IDH2 R172
    |
    Idylla™ IDH1-2 Mutation Assay
    |
    Tibsovo (ivosidenib) • Idhifa (enasidenib) • Voranigo (vorasidenib)
    10ms
    Clinical features and management of germline CEBPA-mutated carriers. (PubMed, Leuk Res)
    Among the 27 healthy germline CEBPA-mutated carriers, we detected a pre-leukemia clone harboring a pathogenic IDH2 variant (R140Q)in one individual. These findings should aid in the genetic counseling and management of AML patients and healthy carriers with germline CEBPA mutations.
    Journal
    |
    IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • CEBPA (CCAAT Enhancer Binding Protein Alpha)
    |
    CEBPA mutation • IDH2 R140Q
    10ms
    A Study of HMPL-306 in Advanced Hematological Malignancies With mIDH (clinicaltrials.gov)
    P1, N=75, Recruiting, Hutchmed | Trial completion date: Sep 2023 --> Jun 2025 | Trial primary completion date: Sep 2023 --> Sep 2024
    Trial completion date • Trial primary completion date • Metastases
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH1 R132H • IDH2 R172K • IDH1 R132C • IDH1 R132 • IDH2 R140Q • IDH2 R172
    |
    HMPL-306
    10ms
    IDH2/R140Q mutation confers cytokine-independent proliferation of TF-1 cells by activating constitutive STAT3/5 phosphorylation. (PubMed, Cell Commun Signal)
    The autocrine cytokines, including GM-CSF, LIF, and OSM, contribute to constitutive STAT3/5 activation in TF-1(R140Q) cells, thereby modulating IDH2/R140Q-mediated malignant proliferation in TF-1 cells. Targeting STAT3/5 phosphorylation may be a novel strategy for the treatment of AML in patients harboring the IDH2/R140Q mutation. Video Abstract.
    Journal
    |
    IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • IL6 (Interleukin 6) • LIF (LIF Interleukin 6 Family Cytokine)
    |
    IDH2 mutation • CSF2 expression • IDH2 R140Q • IL6 expression
    11ms
    Olaparib in Treating Patients With Advanced Glioma, Cholangiocarcinoma, or Solid Tumors With IDH1 or IDH2 Mutations (clinicaltrials.gov)
    P2, N=145, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting
    Enrollment closed
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH2 mutation • IDH1 R132H • IDH2 R172K • IDH1 R132C • IDH1 R132 • IDH1 R132G • IDH2 R140Q • IDH1 R132L • IDH1 R132S • IDH1 R132V • IDH2 R172 • IDH2 R172G
    |
    Lynparza (olaparib)
    11ms
    Targeting IDH2R140Q and other neoantigens in acute myeloid leukemia. (PubMed, Blood)
    These neo-T cells could selectively recognize and kill HLA-matched AML targets endogenously expressing IDH2R140Q both in vitro and in vivo. Overall, our findings support the clinical translation of neoantigen-specific T cells to treat R/R AML.
    Journal • IO biomarker
    |
    CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule)
    |
    IDH1 R132 • IDH2 R140Q
    1year
    NCI-2019-03057: Using the Anticancer Drug Olaparib to Treat Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome With an Isocitrate Dehydrogenase (IDH) Mutation (clinicaltrials.gov)
    P2, N=94, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024
    Trial completion date • Trial primary completion date
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH2 mutation • IDH1 R132H • IDH2 R172K • IDH1 R132C • IDH wild-type • IDH1 R132 • IDH1 R132G • IDH2 R140Q • IDH1 R132L • IDH1 R132S • IDH1 R132V • IDH2 R172 • IDH2 R172G
    |
    Lynparza (olaparib)
    1year
    NCI-2019-03057: Using the Anticancer Drug Olaparib to Treat Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome With an Isocitrate Dehydrogenase (IDH) Mutation (clinicaltrials.gov)
    P2, N=94, Recruiting, National Cancer Institute (NCI) | Active, not recruiting --> Recruiting
    Enrollment open
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH2 mutation • IDH1 R132H • IDH2 R172K • IDH1 R132C • IDH1 R132 • IDH1 R132G • IDH2 R140Q • IDH1 R132V • IDH2 R172 • IDH2 R172G
    |
    Lynparza (olaparib)
    1year
    Development of a Closed System qPCR Assay to Detect Mutations in IDH1/IDH2 in Patients with Acute Myeloid Leukemia (AML) (ASH 2023)
    Additionally, several IDH1/IDH2 inhibitors such as ivosidenib and enasidenib have been approved by the FDA for treatment of AML patients with IDH1 and IDH2 mutations respectively. We have prototyped 18-plex assay designed to detect 7 IDH1 and 10 IDH2 mutations and call out its corresponding codon in EDTA whole blood samples using a single cartridge at an estimated LoD of 1%.
    Clinical
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH1 mutation • IDH2 mutation • IDH1 R132H • IDH2 R172K • IDH1 R132C • IDH1 R132 • IDH2 R140Q • IDH2 R140 • IDH2 R172
    |
    Tibsovo (ivosidenib) • Idhifa (enasidenib)
    1year
    Development of a Fully Immunocompetent Adoptive Transfer In Vivo Model of Npm1cA; Idh2R140Q; Flt3ITD AML (ASH 2023)
    Mice received daily oral gavage of either vehicle, 100 mg/kg venetoclax (BCL2 inhibitor), 100 mg/kg enasidenib (IDH2 inhibitor) or 30 mg/kg gilteritinib (FLT3 inhibitor). Adoptive transfer of splenocytes into either immunodeficient NCG or fully immunocompetent PepBoy recipients faithfully recapitulates the disease of primary mice in a reproducible manner. This model therefore provides an in vivo model conducive to drug development studies and provides the opportunity to understand the impact of both AML development and therapeutics on the normal immune system.
    Preclinical • IO biomarker
    |
    FLT3 (Fms-related tyrosine kinase 3) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • ITGAM (Integrin, alpha M) • PRKDC (Protein Kinase, DNA-Activated, Catalytic Subunit)
    |
    FLT3-ITD mutation • IDH2 R140Q
    |
    Venclexta (venetoclax) • Xospata (gilteritinib) • Idhifa (enasidenib)
    1year
    Final Results of the Phase Ib/II Study Evaluating Enasidenib in Combination with Venetoclax in Patients with IDH2-Mutated Relapsed/Refractory Myeloid Malignancies (ASH 2023)
    Almost all pts had AML, except one with MDS who progressed on treatment with azacitidine. The combination of ENA and VEN is safe and well tolerated in pts with R/R mIDH2 myeloid malignancies. The ENA-VEN combination compares favorably to ENA single-agent in this patient population. Further studies of targeted combination therapies using IDH2 and BCL2 inhibitors are warranted.
    Clinical • P1/2 data • Combination therapy • IO biomarker
    |
    IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH2 mutation • IDH2 R172K • IDH2 R140Q • IDH2 R140 • IDH2 R172
    |
    Venclexta (venetoclax) • azacitidine • Idhifa (enasidenib)
    1year
    Evaluation of the Idylla Rapid IDH1/2 Mutation Assay in FFPE glioma samples (AMP 2023)
    The Idylla Rapid IDH1/2 Mutation Assay had 92% concordance with NGS for FFPE sections. Compared with Idylla EGFR and KRAS assays (previously published) both control and target Cqs were considerably higher using the same number of sections or amount of DNA. A large DNA input requires stewardship for effective tissue utilization for molecular testing, especially in glioma biopsy samples, which may be limited.
    EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH1 mutation • IDH2 mutation • IDH1 R132H • IDH2 R172K • IDH1 R132C • IDH wild-type • IDH1 R132 • IDH2 R140Q • IDH2 R140 • IDH2 R172
    |
    Idylla™ EGFR Mutation Test • Idylla™ KRAS Mutation Test
    1year
    NCI-2019-03057: Using the Anticancer Drug Olaparib to Treat Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome With an Isocitrate Dehydrogenase (IDH) Mutation (clinicaltrials.gov)
    P2, N=94, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting
    Enrollment closed
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH2 mutation • IDH1 R132H • IDH2 R172K • IDH1 R132C • IDH1 R132 • IDH1 R132G • IDH2 R140Q • IDH1 R132V • IDH2 R172 • IDH2 R172G
    |
    Lynparza (olaparib)
    over1year
    An integrative computational approach for the identification of dual inhibitors of isocitrate dehydrogenase 1 and 2 from phytocompounds of Phyllantus amarus. (PubMed, J Biomol Struct Dyn)
    Ultimately, ellagic acid and pinoresinol were identified as promising hits for the development of IDH1_R132H and IDH2_R140Q dual inhibitors. However, further experimental studies are needed to confirm their potential as therapies.Communicated by Ramaswamy H. Sarma.
    Journal
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH1 mutation • IDH1 R132H • IDH1 R132 • IDH2 R140Q
    over1year
    Olaparib in Treating Patients With Advanced Glioma, Cholangiocarcinoma, or Solid Tumors With IDH1 or IDH2 Mutations (clinicaltrials.gov)
    P2, N=145, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2023 --> Jul 2024 | Trial primary completion date: Jul 2023 --> Jul 2024
    Trial completion date • Trial primary completion date • Metastases
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH2 mutation • IDH1 R132H • IDH2 R172K • IDH1 R132C • IDH1 R132 • IDH1 R132G • IDH2 R140Q • IDH1 R132V • IDH2 R172 • IDH2 R172G
    |
    Lynparza (olaparib)
    over1year
    Severe Systemic Auto-Inflammation in an Elderly Woman with Clonal Hematopoiesis (AMP Europe 2023)
    The discovery of clonal hematopoiesis in this elderly woman with a wide spectrum of severe auto-inflammatory conditions supports a potentially intriguing link between somatic blood mutations and her adult- onset rheumatologic disorders. Mechanistically, disrupted SRSF2-mediated splicing may be driving aberrant antigen presentation by bone marrow-derived dendritic cells in her skin and other organs. Causal relationships between somatic blood mutations and autoimmune/auto-inflammatory conditions have been established in patients with hematologic malignancies and conditions like VEXAS syndrome.
    Clinical
    |
    MAP2K1 (Mitogen-activated protein kinase kinase 1) • SRSF2 (Serine and arginine rich splicing factor 2)
    |
    IDH2 mutation • SRSF2 mutation • MAP2K1 C121S • IDH2 R140Q • SRSF2 P95L • IDH2 mutation + SRSF2 mutation
    |
    Oncomine Focus Assay • Oncomine Myeloid Assay GX • TruSight Myeloid Sequencing Panel
    over1year
    A PHASE 1 STUDY OF HMPL-306, A DUAL INHIBITOR OF MUTANT ISOCITRATE DEHYDROGENASE (IDH) 1 AND 2, IN PTS WITH RELAPSED/REFRACTORY MYELOID HEMATOLOGICAL MALIGNANCIES HARBORING IDH1 AND/OR 2 MUTATIONS (EHA 2023)
    Combing with safety, tolerability, PK/PD and preliminary efficacy, the RP2D was set as 250 mg QD at Cycle 1, and then with 150 mg QD from Cycle 2. Dose expansion is ongoing. Clinical trialinformation: NCT04272957.
    Clinical • P1 data
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH1 mutation • IDH2 mutation • IDH2 R172K • IDH1 R132C • IDH1 R132 • IDH2 R140Q • IDH2 R172
    |
    HMPL-306
    over1year
    A Study of HMPL-306 in Advanced Hematological Malignancies With mIDH (clinicaltrials.gov)
    P1, N=75, Recruiting, Hutchmed | Trial completion date: Jan 2023 --> Sep 2023 | Trial primary completion date: Jan 2023 --> Sep 2023
    Trial completion date • Trial primary completion date
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH1 R132H • IDH2 R172K • IDH1 R132C • IDH1 R132 • IDH2 R140Q • IDH2 R172
    |
    HMPL-306
    almost2years
    Preclinical characteristic of HMPL-306, a CNS-penetrable dual inhibitor of mutant IDH1 and IDH2 (AACR 2023)
    Oral administration of HMPL-306 remarkably decreased 2-HG level in plasma and tumor tissues in xenograft models carrying mIDH1 or mIDH2 and the inhibition is more potent and durable than either ivosidenib or enasidenib at the same dose...Combination treatment of HMPL-306 and azacitidine synergized in releasing the differentiation block in mIDH AML cells. HMPL-306 is a potent, dual inhibitor of IDH1/2 mutation. The strong activity and favorable PK profiles support further clinical evaluation.
    Preclinical
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH1 mutation • IDH2 mutation • IDH1 R132H • IDH2 R172K • IDH wild-type • IDH1 R132 • IDH2 R140Q • IDH2 R172
    |
    azacitidine • Tibsovo (ivosidenib) • Idhifa (enasidenib) • HMPL-306
    almost2years
    Natural and Synthetic 2-Oxogluturate Derivatives are Substrates for Oncogenic Variants of Human Isocitrate Dehydrogenase 1 and 2. (PubMed, J Biol Chem)
    Furthermore, NMR and mass spectrometry studies confirmed IDH1/2 variant-catalyzed production of alcohols in the cases of the 3-methyl-, 3-butyl-, and 3-benzyl-substituted 2OG derivatives; a crystal structure of 3-butyl-2OG with an IDH1 variant (R132C/S280F IDH1) reveals active site binding. The combined results highlight the potential for (i) IDH1/2 variant-catalyzed reduction of 2-oxoacids other than 2OG in cells, (ii) modulation of IDH1/2 variant activity by 2-oxoacid natural products, including some present in common foods, (iii) inhibition of IDH1/2 variants via active site binding rather than the established allosteric mode of inhibition, and (iv) possible use of IDH1/2 variants as biocatalysts.
    Journal
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH1 R132H • IDH2 R172K • IDH1 R132C • IDH wild-type • IDH1 R132 • IDH2 R140Q • IDH2 R172
    almost2years
    Acute Myeloid Leukemia with CEBPA Mutation: Next-Generation Sequencing-Based Computational Approach For Enhancing the Diagnosis of Patients with Potential Germline CEBPA Mutated Predisposition (USCAP 2023)
    Recognizing and referring patients with possible germline mutations for appropriate genetic evaluation and testing provides insight into best patient care strategies along with education and testing opportunities for family members. Leukemia based NGS panels may aid as screening tools for detecting potential pathogenic germline variants.
    Clinical • Next-generation sequencing
    |
    FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • KMT2C (Lysine Methyltransferase 2C) • WT1 (WT1 Transcription Factor) • BCOR (BCL6 Corepressor) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • CD36 (thrombospondin receptor) • MSH3 (MutS Homolog 3) • GATA2 (GATA Binding Protein 2) • PHF6 (PHD Finger Protein 6) • BCORL1 (BCL6 Corepressor Like 1)
    |
    NRAS Q61 • CEBPA mutation • NRAS G13 • NRAS Q61L • DNMT3A R882H • IDH1 R132 • NRAS G13D • NRAS G13R • IDH2 R140Q • DNMT3A R882 • NPM1 W288
    |
    FoundationOne® Heme CDx
    2years
    Exploration of natural product database for the identification of potent inhibitor against IDH2 mutational variants for glioma therapy. (PubMed, J Mol Model)
    To date, enasidenib is the only FDA-approved drug widely used as a mIDH2 (R140Q) inhibitor...Indeed, the reproducibility and significance of our results are examined by running 3 replicas of 100-ns simulations per system using the random initial velocities of the atoms generated by Maxwell distribution at a given temperature. Thus, we hypothesize from our results that further optimization of squalene could be beneficial for the treatment and management of glioma in the near future.
    Journal
    |
    IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH2 mutation • IDH2 R140Q
    |
    Idhifa (enasidenib)
    2years
    NCI-2019-03057: Using the Anticancer Drug Olaparib to Treat Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome With an Isocitrate Dehydrogenase (IDH) Mutation (clinicaltrials.gov)
    P2, N=94, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2022 --> Dec 2023
    Trial completion date • Trial primary completion date
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
    |
    IDH2 mutation • IDH1 R132H • IDH2 R172K • IDH1 R132C • IDH1 R132 • IDH1 R132G • IDH2 R140Q • IDH1 R132V • IDH2 R172 • IDH2 R172G
    |
    Lynparza (olaparib)
    2years
    Effects of cancer-associated point mutations on the structure, function, and stability of isocitrate dehydrogenase 2. (PubMed, Sci Rep)
    Using overlapping PCR, transfection, immunoblotting, immunoprecipitation, measurements of enzyme activity, glucose, lactic acid, ATP, and reactive oxygen species (ROS), cell viability, protein degradation assays post-inhibition of the 26S proteasome (bortezomib) or HSP90 (17-AAG), and a homology model, we demonstrated that the properties of ten cancer-associated IDH2 variants (R140G/Q/W and R172S/K/M/W/G/C/P) arising from point mutations are closely related to their structure and stability...The homology model further revealed that changes in conformation and IDH2 protein stability appeared to be associated with these point mutations. Taken together, our findings provide information important for understanding the molecular mechanisms of IDH2 mutations in tumors.
    Journal
    |
    IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • CCND1 (Cyclin D1) • IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1Heat Shock Protein 90 Alpha Family Class A Member 1)
    |
    IDH2 mutation • IDH2 R172K • CCND1 expression • IDH wild-type • IDH2 R140Q • IDH2 R140 • IDH2 R172 • IDH2 R172G • IL6 expression • IDH2 overexpression
    |
    bortezomib
    2years
    Evaluating Stem Cells to Predict Post-Transplant Relapse in the Myelodysplastic Syndromes (ASH 2022)
    Validation of this assay in larger cohorts promises to yield a tool to identify patients who may benefit from early post-transplant interventions to forestall relapse. We also demonstrate how this assay can reveal novel insights into human disease HSC biology.
    IO biomarker
    |
    TP53 (Tumor protein P53) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • DNMT3A (DNA methyltransferase 1) • ASXL1 (ASXL Transcriptional Regulator 1) • CD38 (CD38 Molecule) • CD34 (CD34 molecule) • DDX41 (DEAD-Box Helicase 41)
    |
    TP53 mutation • ASXL1 mutation • DDX41 mutation • DNMT3A R882H • IDH2 R140Q • TP53 Y220C • DNMT3A R882
    2years
    Phase I Study of TQB3455, a Selective Inhibitor of IDH2 with Favorable Safety and More Potent Efficacy to IDH2-R172K Mutation, for Acute Myeloid Leukemia and Myelodysplastic Syndrome (ASH 2022)
    Enasidenib (ENA), the first selective IDH2 inhibitor, was associated with impressive response rates in relapsed/refractory (R/R) AML and was approved by FDA in 2017. TQB3455 is well-tolerated for myeloid malignancy at the R2PD of 100 mg qd. It also yield high rates of clinical response in pts with mIDH2 AML. Patients with IDH2-R172K mutation fared much better than IDH2-R140Q/W with regard to response, this is in line with outcome of TQB3455 in vitro but different from previous reports of ENA.
    Clinical • P1 data
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    FLT3 (Fms-related tyrosine kinase 3) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2)
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    IDH2 mutation • RAS mutation • IDH2 R172K • IDH2 R140Q • IDH2 R172
    |
    Idhifa (enasidenib) • TQB3455
    2years
    Targeting IDH1-Mutated Pre-Leukemic Hematopoietic Stem Cells in Myeloid Disease, Including CCUS and AML (ASH 2022)
    These cells were subjected to treatment with DMSO, ivosidenib, enasidenib, or IACS-010759 and subsequently plated for colony formation. The OXPHOS-inhibitor IACS-010759 can eradicate IDH1-mutated pHSCs whereas ivosidenib cannot. This effect is specific for IDH1 mutations and the same effect is not seen in IDH2-mutated pHSCs. These results have potential clinical implications when considering therapeutic options in AML as well as IDH1-mutated pre-leukemic conditions such as CCUS.
    IO biomarker
    |
    IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • CD20 (Membrane Spanning 4-Domains A1) • CD19 (CD19 Molecule) • CD38 (CD38 Molecule) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • CD34 (CD34 molecule) • CD99 (CD99 Molecule)
    |
    IDH1 mutation • IDH2 mutation • IDH1 R132H • IDH wild-type • IDH1 R132 • IDH2 R140Q
    |
    Tibsovo (ivosidenib) • Idhifa (enasidenib) • IACS-010759