# Epigenetic therapy roadmap: loosening silenced genes → mutation-specific enzymes → editing the epigenome

Source: https://onco.cc/roadmaps/epigenetics-roadmap/  
OnCo record `epigenetics-roadmap` (Roadmap). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Epigenetic drugs change how genes are read rather than the genes themselves. They started as gentle chemotherapy for blood cancers and are becoming precise drugs against the enzymes and scaffolds that particular cancers depend on.

## Summary

The first epigenetic drugs were blunt: hypomethylating agents (azacitidine, decitabine) that strip chemical off-switches from DNA and HDAC inhibitors that loosen its packaging. They earned their place in myelodysplastic syndromes, acute myeloid leukaemia and T-cell lymphomas, and azacitidine plus venetoclax became the standard for older patients with AML (VIALE-A). The second generation is mutation-specific: IDH1 and IDH2 inhibitors for leukaemia, bile duct cancer and low-grade glioma (vorasidenib), the EZH2 inhibitor tazemetostat for epithelioid sarcoma and follicular lymphoma, and the menin inhibitors revumenib (2024) and ziftomenib (2025) for leukaemias driven by KMT2A rearrangements or NPM1 mutations.

The frontier is solid tumours and the transcriptional machinery itself: EZH2 inhibition to re-sensitise prostate cancer to hormone therapy (MEVPRO-1), PRMT5 inhibitors for the tenth of tumours lacking MTAP, degraders that remove transcription factors previously thought undruggable, and epigenetic editing that silences a gene durably without cutting DNA.

The pace is set by the undruggable nature of many epigenetic targets, by resistance that emerges through the same plasticity the drugs exploit, and by the difficulty of finding a biomarker for a mechanism that is not a mutation.

## Fields

- Kind: Roadmap
- Last checked: 2026-09-10

## Sources

- Baylin and Jones, Epigenetic determinants of cancer (Cold Spring Harbor Perspectives 2016): https://doi.org/10.1101/cshperspect.a019505
- AUGMENT-101: revumenib (Nature 2023): https://doi.org/10.1038/s41586-023-05812-3

## Connected records

- ideas: [Degraders for the fusion proteins that drive childhood sarcomas](https://onco.cc/ideas/idea-bio1-fusion-tf-degraders/)
- companies: [Arpeggio Bio](https://onco.cc/companies/arpeggio-bio/), [Chipscreen Biosciences](https://onco.cc/companies/chipscreen/), [K36 Therapeutics](https://onco.cc/companies/k36-therapeutics/), [MorphoSys (Novartis)](https://onco.cc/companies/morphosys/)
- key papers: [AUGMENT-101: revumenib, the first menin inhibitor, in relapsed leukaemias driven by KMT2A rearrangement or NPM1 mutation](https://onco.cc/key-papers/paper-augment-101-revumenib-menin-nature-2023/), [Epigenetic Determinants of Cancer](https://onco.cc/key-papers/paper-baylin-cold-spring-harb-perspect-biol/), [Hallmarks of Cancer 2022: adding phenotypic plasticity, epigenetic reprogramming, microbiomes and senescent cells](https://onco.cc/key-papers/paper-hallmarks-new-dimensions-cancer-discov-2022/), [INDIGO: vorasidenib, the first targeted drug for IDH-mutant low-grade glioma](https://onco.cc/key-papers/paper-indigo-nejm-2023/), [VIALE-A: venetoclax plus azacitidine for older adults with acute myeloid leukaemia who cannot have intensive chemotherapy](https://onco.cc/key-papers/paper-viale-a-venetoclax-azacitidine-nejm-2020/)
- roadmaps: [Radical oncology: what could change the war by 2035](https://onco.cc/roadmaps/frontier-2035/), [Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall](https://onco.cc/roadmaps/targeted-therapy-roadmap/)
- fronts: [Epigenetic & Transcriptional Therapy](https://onco.cc/fronts/epigenetics/)
- technologies: [DNA methylation profiling](https://onco.cc/technologies/methylation-profiling/), [Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)](https://onco.cc/technologies/epigenetic-drugs/), [Epigenetic editing (durable gene silencing)](https://onco.cc/technologies/epigenetic-editing/), [PROTACs & molecular glues (targeted protein degradation)](https://onco.cc/technologies/protac-degrader/)
- targets: [EZH2](https://onco.cc/targets/ezh2/), [Histone deacetylases (HDAC)](https://onco.cc/targets/hdac/), [IDH1 / IDH2](https://onco.cc/targets/idh/), [Menin](https://onco.cc/targets/menin/), [PRMT5 (MTAP-deleted cancers)](https://onco.cc/targets/prmt5-mtap/)
- drugs: [Azacitidine](https://onco.cc/drugs/azacitidine/), [Belinostat](https://onco.cc/drugs/belinostat/), [Decitabine](https://onco.cc/drugs/decitabine/), [Decitabine + cedazuridine (oral)](https://onco.cc/drugs/decitabine-cedazuridine/), [Enasidenib](https://onco.cc/drugs/enasidenib/), [Eprenetapopt](https://onco.cc/drugs/eprenetapopt/), [Golcadomide](https://onco.cc/drugs/golcadomide/), [Ivosidenib](https://onco.cc/drugs/ivosidenib/), [Mevrometostat](https://onco.cc/drugs/mevrometostat/), [Olutasidenib](https://onco.cc/drugs/olutasidenib/), [Panobinostat](https://onco.cc/drugs/panobinostat/), [Revumenib](https://onco.cc/drugs/revumenib/), [Romidepsin](https://onco.cc/drugs/romidepsin/), [Tazemetostat](https://onco.cc/drugs/tazemetostat/), [Tucidinostat (chidamide)](https://onco.cc/drugs/tucidinostat/), [Venetoclax](https://onco.cc/drugs/venetoclax/), [Vorasidenib](https://onco.cc/drugs/vorasidenib/), [Vorinostat](https://onco.cc/drugs/vorinostat/), [Ziftomenib](https://onco.cc/drugs/ziftomenib/)
- pathways: [Epigenetic reprogramming](https://onco.cc/pathways/epigenetic-reprogramming/), [Menin / KMT2A (HOXA9-MEIS1 axis)](https://onco.cc/pathways/menin-kmt2a/), [Mutant IDH / 2-hydroxyglutarate](https://onco.cc/pathways/idh-2hg/), [MYC](https://onco.cc/pathways/myc/), [SWI/SNF chromatin remodelling](https://onco.cc/pathways/swi-snf-chromatin/), [Transcriptional machinery & addiction](https://onco.cc/pathways/transcription-addiction/)
- terms: [Hallmark (2022): non-mutational epigenetic reprogramming](https://onco.cc/terms/nonmutational-epigenetic-reprogramming/), [Hypomethylating agents (azacitidine, decitabine)](https://onco.cc/terms/hma/)
- trials: [AGILE](https://onco.cc/trials/agile/), [AUGMENT-101](https://onco.cc/trials/augment-101/), [ClarIDHy](https://onco.cc/trials/claridhy/), [GOLSEEK-1](https://onco.cc/trials/golseek-1/), [KOMET-001](https://onco.cc/trials/komet-001/), [MEVPRO-1](https://onco.cc/trials/mevpro-1/), [VIALE-A](https://onco.cc/trials/viale-a/)
- people: [Christopher R. Vakoc](https://onco.cc/people/christopher-vakoc/), [Courtney D. DiNardo](https://onco.cc/people/courtney-dinardo/), [Eytan M. Stein](https://onco.cc/people/eytan-stein/), [Ghayas C. Issa](https://onco.cc/people/ghayas-issa/), [Ingo K. Mellinghoff](https://onco.cc/people/ingo-mellinghoff/), [Pierre Fenaux](https://onco.cc/people/pierre-fenaux/), [Stephen B. Baylin](https://onco.cc/people/stephen-baylin/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/), [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)

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JSON: https://onco.cc/api/v1/entities/epigenetics-roadmap.json