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A metabolic enzyme whose mutant form produces a molecule that scrambles how genes are read; blocking it slows brain tumours and leukaemias. This dossier gathers the 8 products (5 approved), 17 trials, 5 pathways and 0 resistance routes in the corpus that involve it, with external identifiers so it can be joined to UniProt, ChEMBL, Open Targets and the rest of biology.
Neomorphic enzyme activity; 2-HG inhibits TET and histone demethylases.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Glioma & glioblastoma | 70-80% | IDH1/2 mutation in grade 2-3 glioma | <10% in primary glioblastoma | cBioPortal (TCGA) |
| Acute myeloid leukaemia | 15-20% | IDH1 or IDH2 mutation | cBioPortal (TCGA) | |
| Biliary tract cancer | 10-20% | IDH1 mutation (intrahepatic) | cBioPortal (TCGA) | |
| Prostate cancer | 0.5-1% | Hotspot mutation defining a methylator subtype | cBioPortal: 5 of 494, 1.0%, in prad_tcga_pan_can_atlas_2018 (2 R132C, 1 R132G, 1 R132H); 9 of 1,013, 0.9%, in prad_p1000; 14 of 2,260, 0.6%, in prostate_msk_2024; 3 of 477, 0.6%, in prad_cpcg_2017. The TCGA taxonomy put it at 1% of 333 primary tumours and showed the IDH1-mutant subset carried a methylator phenotype (Cancer Genome Atlas Research Network 2015). | cBioPortal (TCGA) |
| Gallbladder cancer | 0.4% | Mutation | IDH1 mutation in 1 of 244 samples, 0.4%, and no IDH2 mutation in cBioPortal gbc_mskcc_2022; 2 of 103 and 1 of 103 in gbc_msk_2018. | cBioPortal (TCGA) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
| Residue | Kind | How common | What it does | Addressed by | Defeats | Source |
|---|---|---|---|---|---|---|
| R132H 132 | Other | About 90% of IDH1 mutations in glioma | Neomorphic: the mutant enzyme makes 2-hydroxyglutarate. R132H is the glioma allele; R132C is more common in AML and cholangiocarcinoma. | - | Yan et al., NEJM 2009 | |
| R132C / R132G / R132S / R132L 132 | Other | not sourced | Non-H alleles enriched in AML, cholangiocarcinoma and chondrosarcoma; covered by the same inhibitors. | - | COSMIC: IDH1 | |
| IDH2 R140Q / R172K (paired gene) 140 | Other | not sourced | Shown for reference at the equivalent IDH1 coordinate: enasidenib covers IDH2; vorasidenib covers both enzymes in glioma. | - | COSMIC: IDH2 |
Frequencies are quoted from the source on each row; a blank means no figure was sourced, not that it is rare. Domain boundaries are approximate. Sources for the map: Cancer Hotspots (MSK) · COSMIC: IDH1.
| Modality | Approved | Phase 3 |
|---|---|---|
| Small molecule 7 | ||
| Test or device 1 | - |
| Trial | Setting | Result | Products | ||
|---|---|---|---|---|---|
INDIGO NCT04164901 | 3 | Positive | Residual or recurrent grade 2 IDH-mutant astrocytoma or oligodendroglioma after surgery, no prior RT/chemo: vorasidenib vs placebo | PFS 27.7 vs 11.1 months, HR 0.39. | |
AGILE NCT03173248 | 3 | Positive | Newly diagnosed IDH1-mutated AML unfit for intensive chemotherapy: ivosidenib + azacitidine vs placebo + azacitidine | OS 24.0 vs 7.9 months; HR 0.44. | |
ClarIDHy NCT02989857 | 3 | Positive | Previously treated IDH1-mutant cholangiocarcinoma: ivosidenib vs placebo | PFS HR 0.37; crossover-adjusted OS HR 0.49. | |
| 3 | Active | A Randomized, Double-blind, Placebo-controlled, Multicenter Phase III Study to Evaluate the Efficacy and Safety of TQB3454 Tablets in the Treatment of Advanced Biliary Tract Cancer With Isocitrate Dehydrogenase 1 (IDH1) Mutation | - | ||
| 3 | Recruiting | A Multicenter, Randomized, Open-Label, Phase III Clinical Study to Evaluate the Efficacy and Safety of HMPL-306 vs. Salvage Chemotherapy Regimens in Patients With IDH1- and IDH2-mutated Relapsed/Refractory Acute Myeloid Leukemia (R/R AML) | - | ||
| 3 | Active | An Open-Label Early Access Phase 3b Study of Ivosidenib in Patients With a Pretreated Locally Advanced or Metastatic Cholangiocarcinoma | - | ||
| 3 | Recruiting | A Single Arm, Open-label Phase 3b Study to Describe the Safety and Tolerability of Ivosidenib in Combination With Azacitidine in Adult Patients Newly Diagnosed With IDH1m Acute Myeloid Leukemia (AML) Ineligible for Intensive Induction Chemotherapy | - | ||
| 3 | Planned | Investigating Precision Medicine in the Adjuvant Setting: a Phase 3 Clinical Trial in Biliary Tract Cancer | - | ||
| 3 | Recruiting | A Phase 3, Multicenter, Double-blind, Randomized, Placebo-controlled Study of Ivosidenib in Participants ≥18 Years of Age With Locally Advanced or Metastatic Conventional Chondrosarcoma With an IDH1 Mutation, Untreated or Previously Treated With 1 Systemic Treatment Regimen | - | ||
SAFIR-ABC10 NCT05615818 | 3 | Recruiting | Advanced biliary cancer (intrahepatic, perihilar or distal cholangiocarcinoma, or gallbladder carcinoma) after induction gemcitabine and cisplatin: molecular targeted maintenance therapy matched to the tumour's alteration versus standard of care, international platform phase 3 | - | |
| 3 | Recruiting | A Phase 3, Multicenter, Clinical Study to Evaluate the Efficacy and Safety of Safusidenib Erbumine in Participants With Isocitrate Dehydrogenase 1 (IDH1)-Mutant Glioma | - | ||
NCI-COG Pediatric MATCH (APEC1621) NCT03155620 | platform | Active | Relapsed or refractory solid tumours, non-Hodgkin lymphomas and histiocytic disorders, age 1-21: tumour sequencing then assignment to one of a dozen single-agent targeted-therapy phase 2 arms | Actionable alteration in 31.5% of the first 1,000 tumours; 28.4% assigned and 13.1% enrolled on a treatment arm. | |
Beat AML Master Trial NCT03013998 | platform | Recruiting | Newly diagnosed acute myeloid leukaemia in patients aged 60 and over: cytogenetic and genomic results returned within seven days assign each patient to a mutation-defined sub-study of targeted therapy, alone or with azacitidine or venetoclax | Genomic assignment within seven days was feasible; patients treated on Beat AML sub-studies had median overall survival of 12.8 months against 3.9 months for those choosing standard care (non-randomised comparison). | |
| 2 | Active | A Phase II Study of DS-1001b in Patients With Chemotherapy- and Radiotherapy-naive IDH1 Mutated WHO Grade II Glioma | - | ||
| 2 | Recruiting | An Exploratory Study on the Use of Ivosidenib for the Precise Treatment of Advanced Biliary Tract Malignancies With IDH1 Mutations in the Later Line of Therapy. | - | ||
| 2 | Planned | A Prospective, Single-arm, Single-center, Phase II Clinical Study of Ivosidenib (AK112) Combined With CapeOX and Radiotherapy in Patients With Unresectable Metastatic MSS-type Colorectal Cancer: Efficacy and Safety Assessment | - | ||
| 2 | Recruiting | Phase 2 Study of Olutasidenib With Temozolomide as Maintenance Therapy in Pediatric and Young Adult Patients Newly Diagnosed With High-Grade Glioma (HGG), Including Diffuse Intrinsic Pontine Glioma (DIPG), Which Harbor IDH1 Mutations | - |
No recorded escape route names this target.
Cancer cells rewire how they eat. They burn glucose inefficiently but fast (the Warburg effect), gorge on glutamine and fats, and build the nucleotides and lipids needed to divide. This is why the FDG PET scan works, and why metabolism is a drug target.
Which nodes have drugs →Cancer changes not just its genes but how they are read: chemical tags on DNA and histones silence guardians and awaken growth programmes. Unlike mutations, these changes are reversible, which is the hope behind epigenetic drugs.
Which nodes have drugs →This KEGG map shows the two genetic roads to glioblastoma: primary tumours amplify EGFR and lose PTEN and p16, secondary tumours from lower-grade astrocytomas over-express PDGF and CDK4 and lose TP53 and RB. It explains why growth-factor and cell-cycle drugs are the main targeted options in brain tumours, and why paediatric low-grade gliomas with BRAF changes respond to MAPK inhibitors.
Which nodes have drugs →After glucose, glutamine is the tumour's favourite food. It feeds the energy cycle, donates nitrogen for making DNA letters, and makes the antioxidant glutathione. MYC- and KRAS-driven cancers eat so much of it that they starve the T cells next door.
Which nodes have drugs →A single mutation in a metabolic enzyme (IDH1 or IDH2) makes cells pour out a molecule they should never make, 2-hydroxyglutarate. It jams the machinery that erases chemical marks on DNA and histones, so blood and brain cells get stuck before they mature. Pills that block the mutant enzyme let them mature again.
Which nodes have drugs →| Assay | Platform | Cut-off | Gates |
|---|---|---|---|
| FoundationOne CDx Foundation Medicine (Roche) · FDA CDx 2017 | NGS tissue | Per companion claim: EGFR, ALK, BRAF V600, ERBB2 amplification, KRAS wild-type, BRCA1/2 and HRR genes, PIK3CA, MET exon 14, RET, FGFR2 fusions, IDH1, NTRK fusions; MSI-high; TMB at least 10 mutations per megabase | |
| Abbott RealTime IDH1 Abbott Molecular · FDA CDx 2018 | PCR | Mutation detected (ivosidenib, AML) | |
| Abbott RealTime IDH2 Abbott Molecular · FDA CDx 2017 | PCR | Mutation detected (enasidenib, AML) |
| Cell line | Identifiers | Why it is used |
|---|---|---|
| HT-1080 | CVCL_0317 · ACH-000054 | Fibrosarcoma, IDH1 R132C; the most used endogenous mutant-IDH1 line. |
| BT142 | CVCL_D718 | Glioma, IDH1 R132H (hemizygous); one of few IDH-mutant glioma lines that grows. |
| TS603 | CVCL_A5HW | Glioma, IDH1 R132H neurosphere culture. |
| SW1353 | CVCL_0543 · ACH-000418 | Chondrosarcoma, IDH2 R172S. |
| RBE | CVCL_4896 · ACH-001856 | Cholangiocarcinoma, IDH1 R132S. |
| SNU-1079 | CVCL_5008 · ACH-000209 | Cholangiocarcinoma, IDH1 R132C. |
IDH-mutant gliomas are notoriously hard to culture and lose the mutation or growth in vitro; most work uses engineered lines or slow-growing PDX (e.g. the Mayo GBM panel).
Why unresolved. INDIGO enrolled grade 2 patients after surgery only; whether IDH inhibition helps after radiotherapy, in grade 3 disease, or as a way to defer radiotherapy-related cognitive harm is untested.
What would answer it. Trials in grade 3 and post-radiotherapy settings, and a comparison of early vorasidenib versus standard chemoradiotherapy with cognitive endpoints.
Query for this target: (TITLE:"IDH1 / IDH2" OR ABSTRACT:"IDH1 / IDH2" OR TITLE:"IDH1" OR ABSTRACT:"IDH1" OR TITLE:"IDH2" OR ABSTRACT:"IDH2") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about IDH1 / IDH2, not a curated reading list.
The dossier as machine-readable JSON, at /api/v1/dossiers/idh.json: identifiers from HGNC, Ensembl, UniProt and ChEMBL, products with status, trials, pathways, hotspots, open questions and assays. The full entity record is in the open API at /api/v1/entities/idh.json. Licence CC BY-NC 4.0.