{"entity":{"id":"epigenetics-roadmap","kind":"roadmap","name":"Epigenetic therapy roadmap: loosening silenced genes → mutation-specific enzymes → editing the epigenome","aka":[],"tldr":"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.\n\nThe 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.\n\nThe 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.","asOf":"2026-09-10","links":[{"label":"Baylin and Jones, Epigenetic determinants of cancer (Cold Spring Harbor Perspectives 2016)","url":"https://doi.org/10.1101/cshperspect.a019505"},{"label":"AUGMENT-101: revumenib (Nature 2023)","url":"https://doi.org/10.1038/s41586-023-05812-3"}],"tags":[],"related":["idea-bio1-fusion-tf-degraders","k36-therapeutics","arpeggio-bio","morphosys","chipscreen","paper-indigo-nejm-2023","paper-viale-a-venetoclax-azacitidine-nejm-2020","paper-augment-101-revumenib-menin-nature-2023","paper-hallmarks-new-dimensions-cancer-discov-2022","targeted-therapy-roadmap"],"cancers":[],"sections":["epigenetics"],"technologies":["epigenetic-drugs","epigenetic-editing","protac-degrader","methylation-profiling"],"targets":["menin","ezh2","idh","hdac","prmt5-mtap"],"drugs":["azacitidine","decitabine","decitabine-cedazuridine","vorinostat","romidepsin","belinostat","panobinostat","tucidinostat","ivosidenib","enasidenib","olutasidenib","vorasidenib","tazemetostat","revumenib","ziftomenib","venetoclax","mevrometostat","golcadomide","eprenetapopt"],"companies":[],"institutions":[],"pathways":["epigenetic-reprogramming","transcription-addiction","menin-kmt2a","idh-2hg","swi-snf-chromatin","myc"],"terms":["hma","nonmutational-epigenetic-reprogramming"],"trials":["viale-a","agile","augment-101","komet-001","mevpro-1","claridhy","golseek-1"],"people":["stephen-baylin","pierre-fenaux","courtney-dinardo","eytan-stein","ghayas-issa","ingo-mellinghoff","christopher-vakoc"],"bottlenecks":["b-undruggable-targets","b-resistance","b-tumor-heterogeneity","b-biomarker-validation"],"keyPapers":["paper-baylin-cold-spring-harb-perspect-biol"],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1980s-2006","title":"Silenced genes and the drugs that loosen them","description":"Baylin and others showed that abnormal DNA methylation silences tumour-suppressor genes as effectively as a mutation, and that the silencing can be reversed. Azacitidine, an old chemotherapy given at low dose, was approved for myelodysplastic syndromes in 2004 and shown to extend survival (AZA-001); decitabine followed. Vorinostat (2006) was the first HDAC inhibitor, loosening the packaging of DNA in cutaneous T-cell lymphoma.","refs":["stephen-baylin","epigenetic-reprogramming","azacitidine","decitabine","hma","pierre-fenaux","vorinostat","hdac"],"status":"historic"},{"era":"2009-2016","title":"The HDAC class finds its niche, and its limits","description":"Romidepsin and belinostat joined vorinostat in T-cell lymphomas, tucidinostat became China's first original epigenetic drug, and panobinostat was approved in myeloma in 2015 then withdrawn in 2021 when its confirmatory trial was not done. Broad HDAC inhibition proved too toxic and too unselective for solid tumours, which pushed the field towards enzymes that particular cancers depend on.","refs":["romidepsin","belinostat","tucidinostat","chipscreen","panobinostat","epigenetic-drugs"],"status":"historic"},{"era":"2017-2020","title":"Mutation-specific epigenetic drugs","description":"Mutant IDH1 and IDH2 produce a metabolite that scrambles how genes are read; enasidenib (2017) and ivosidenib (2018) block the mutant enzymes, and AGILE showed ivosidenib plus azacitidine sharply extends survival in newly diagnosed IDH1-mutant AML. ClarIDHy brought ivosidenib to bile duct cancer. Tazemetostat (2020) was the first EZH2 inhibitor, for epithelioid sarcoma and follicular lymphoma, until Ipsen withdrew it worldwide in March 2026 over secondary blood cancers. For the first time an epigenetic drug had a molecular biomarker.","refs":["ivosidenib","enasidenib","olutasidenib","agile","claridhy","idh","idh-2hg","tazemetostat","ezh2"],"status":"current"},{"era":"2020-2026","title":"Hypomethylating agents as the backbone","description":"VIALE-A made azacitidine plus venetoclax the standard for older patients with AML who cannot have intensive chemotherapy, doubling remission rates; the hypomethylating agent primes the leukaemia for the BCL-2 inhibitor. Oral azacitidine maintenance and oral decitabine-cedazuridine took the class out of the infusion chair. Every new AML drug is now tested on top of this backbone.","refs":["viale-a","venetoclax","azacitidine","decitabine-cedazuridine","courtney-dinardo","paper-viale-a-venetoclax-azacitidine-nejm-2020"],"status":"current"},{"era":"2023-2026","title":"Menin inhibitors and the first brain tumour epigenetic drug","description":"Certain leukaemias keep their genes switched on through a scaffold protein, menin. Revumenib (2024, AUGMENT-101) created the class for KMT2A-rearranged and NPM1-mutant acute leukaemias and ziftomenib (November 2025, KOMET-001) followed, both as once-daily pills; the resistance mutations in menin itself appeared within the first trials. Vorasidenib (INDIGO, 2023) became the first targeted therapy for IDH-mutant low-grade glioma, delaying radiation and chemotherapy by years.","refs":["revumenib","ziftomenib","augment-101","komet-001","menin","menin-kmt2a","eytan-stein","ghayas-issa","vorasidenib","ingo-mellinghoff","paper-indigo-nejm-2023","paper-augment-101-revumenib-menin-nature-2023"],"status":"current"},{"era":"2026-2030","title":"Solid tumours and the transcriptional machinery","description":"Mevrometostat pairs EZH2 inhibition with enzalutamide in three phase 3 prostate trials (MEVPRO-1). PRMT5 inhibitors exploit the loss of MTAP in about a tenth of all tumours. Golcadomide degrades two lymphoma transcription factors and is in a first-line phase 3 (GOLSEEK-1). Degraders for the fusion transcription factors that drive childhood sarcomas, drugs for broken SWI/SNF complexes, NSD2 inhibitors and BET inhibitors are all in the clinic. Eprenetapopt's failure to refold mutant p53 is the reminder that a compelling mechanism is not a drug.","refs":["mevrometostat","mevpro-1","prmt5-mtap","golcadomide","golseek-1","idea-bio1-fusion-tf-degraders","swi-snf-chromatin","k36-therapeutics","morphosys","eprenetapopt","transcription-addiction","myc","christopher-vakoc"],"status":"emerging"},{"era":"2030+","title":"Writing to the epigenome","description":"Epigenetic editing uses a targeting protein fused to a methylation writer to switch a chosen gene off durably without cutting DNA; it is in first human trials outside oncology and its cancer use depends on solving tumour delivery. In the other direction, hypomethylating agents make tumours more visible to the immune system by re-expressing silenced antigens, an idea being tested in combination with checkpoint blockade. AI models trained on RNA data are hunting drugs against transcription factors directly.","refs":["epigenetic-editing","nonmutational-epigenetic-reprogramming","arpeggio-bio","paper-hallmarks-new-dimensions-cancer-discov-2022","frontier-2035"],"status":"speculative"},{"era":"What sets the pace","title":"Undruggable targets, plasticity and biomarkers","description":"Many epigenetic regulators have no pocket for a small molecule, which is why degraders and glues matter here more than anywhere. The same plasticity the drugs exploit lets tumours change state to escape them. And because the mechanism is not a mutation, finding the patients who will respond is harder: methylation profiling and expression signatures, not gene panels, are the likely biomarkers.","refs":["b-undruggable-targets","b-resistance","b-tumor-heterogeneity","b-biomarker-validation","protac-degrader","methylation-profiling"],"status":"current"}],"watch":[]},"route":"/roadmaps/epigenetics-roadmap/","neighbours":{"idea":[{"id":"idea-bio1-fusion-tf-degraders","kind":"idea","name":"Degraders for the fusion proteins that drive childhood sarcomas","route":"/ideas/idea-bio1-fusion-tf-degraders/"}],"company":[{"id":"arpeggio-bio","kind":"company","name":"Arpeggio Bio","route":"/companies/arpeggio-bio/"},{"id":"chipscreen","kind":"company","name":"Chipscreen Biosciences","route":"/companies/chipscreen/"},{"id":"k36-therapeutics","kind":"company","name":"K36 Therapeutics","route":"/companies/k36-therapeutics/"},{"id":"morphosys","kind":"company","name":"MorphoSys (Novartis)","route":"/companies/morphosys/"}],"paper":[{"id":"paper-augment-101-revumenib-menin-nature-2023","kind":"paper","name":"AUGMENT-101: revumenib, the first menin inhibitor, in relapsed leukaemias driven by KMT2A rearrangement or NPM1 mutation","route":"/key-papers/paper-augment-101-revumenib-menin-nature-2023/"},{"id":"paper-baylin-cold-spring-harb-perspect-biol","kind":"paper","name":"Epigenetic Determinants of Cancer","route":"/key-papers/paper-baylin-cold-spring-harb-perspect-biol/"},{"id":"paper-hallmarks-new-dimensions-cancer-discov-2022","kind":"paper","name":"Hallmarks of Cancer 2022: adding phenotypic plasticity, epigenetic reprogramming, microbiomes and senescent cells","route":"/key-papers/paper-hallmarks-new-dimensions-cancer-discov-2022/"},{"id":"paper-indigo-nejm-2023","kind":"paper","name":"INDIGO: vorasidenib, the first targeted drug for IDH-mutant low-grade glioma","route":"/key-papers/paper-indigo-nejm-2023/"},{"id":"paper-viale-a-venetoclax-azacitidine-nejm-2020","kind":"paper","name":"VIALE-A: venetoclax plus azacitidine for older adults with acute myeloid leukaemia who cannot have intensive chemotherapy","route":"/key-papers/paper-viale-a-venetoclax-azacitidine-nejm-2020/"}],"roadmap":[{"id":"frontier-2035","kind":"roadmap","name":"Radical oncology: what could change the war by 2035","route":"/roadmaps/frontier-2035/"},{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/"}],"section":[{"id":"epigenetics","kind":"section","name":"Epigenetic & Transcriptional Therapy","route":"/fronts/epigenetics/"}],"technology":[{"id":"methylation-profiling","kind":"technology","name":"DNA methylation profiling","route":"/technologies/methylation-profiling/"},{"id":"epigenetic-drugs","kind":"technology","name":"Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)","route":"/technologies/epigenetic-drugs/"},{"id":"epigenetic-editing","kind":"technology","name":"Epigenetic editing (durable gene silencing)","route":"/technologies/epigenetic-editing/"},{"id":"protac-degrader","kind":"technology","name":"PROTACs & molecular glues (targeted protein degradation)","route":"/technologies/protac-degrader/"}],"target":[{"id":"ezh2","kind":"target","name":"EZH2","route":"/targets/ezh2/"},{"id":"hdac","kind":"target","name":"Histone deacetylases (HDAC)","route":"/targets/hdac/"},{"id":"idh","kind":"target","name":"IDH1 / IDH2","route":"/targets/idh/"},{"id":"menin","kind":"target","name":"Menin","route":"/targets/menin/"},{"id":"prmt5-mtap","kind":"target","name":"PRMT5 (MTAP-deleted cancers)","route":"/targets/prmt5-mtap/"}],"drug":[{"id":"azacitidine","kind":"drug","name":"Azacitidine","route":"/drugs/azacitidine/"},{"id":"belinostat","kind":"drug","name":"Belinostat","route":"/drugs/belinostat/"},{"id":"decitabine","kind":"drug","name":"Decitabine","route":"/drugs/decitabine/"},{"id":"decitabine-cedazuridine","kind":"drug","name":"Decitabine + cedazuridine (oral)","route":"/drugs/decitabine-cedazuridine/"},{"id":"enasidenib","kind":"drug","name":"Enasidenib","route":"/drugs/enasidenib/"},{"id":"eprenetapopt","kind":"drug","name":"Eprenetapopt","route":"/drugs/eprenetapopt/"},{"id":"golcadomide","kind":"drug","name":"Golcadomide","route":"/drugs/golcadomide/"},{"id":"ivosidenib","kind":"drug","name":"Ivosidenib","route":"/drugs/ivosidenib/"},{"id":"mevrometostat","kind":"drug","name":"Mevrometostat","route":"/drugs/mevrometostat/"},{"id":"olutasidenib","kind":"drug","name":"Olutasidenib","route":"/drugs/olutasidenib/"},{"id":"panobinostat","kind":"drug","name":"Panobinostat","route":"/drugs/panobinostat/"},{"id":"revumenib","kind":"drug","name":"Revumenib","route":"/drugs/revumenib/"},{"id":"romidepsin","kind":"drug","name":"Romidepsin","route":"/drugs/romidepsin/"},{"id":"tazemetostat","kind":"drug","name":"Tazemetostat","route":"/drugs/tazemetostat/"},{"id":"tucidinostat","kind":"drug","name":"Tucidinostat (chidamide)","route":"/drugs/tucidinostat/"},{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/"},{"id":"vorasidenib","kind":"drug","name":"Vorasidenib","route":"/drugs/vorasidenib/"},{"id":"vorinostat","kind":"drug","name":"Vorinostat","route":"/drugs/vorinostat/"},{"id":"ziftomenib","kind":"drug","name":"Ziftomenib","route":"/drugs/ziftomenib/"}],"pathway":[{"id":"epigenetic-reprogramming","kind":"pathway","name":"Epigenetic reprogramming","route":"/pathways/epigenetic-reprogramming/"},{"id":"menin-kmt2a","kind":"pathway","name":"Menin / KMT2A (HOXA9-MEIS1 axis)","route":"/pathways/menin-kmt2a/"},{"id":"idh-2hg","kind":"pathway","name":"Mutant IDH / 2-hydroxyglutarate","route":"/pathways/idh-2hg/"},{"id":"myc","kind":"pathway","name":"MYC","route":"/pathways/myc/"},{"id":"swi-snf-chromatin","kind":"pathway","name":"SWI/SNF chromatin remodelling","route":"/pathways/swi-snf-chromatin/"},{"id":"transcription-addiction","kind":"pathway","name":"Transcriptional machinery & addiction","route":"/pathways/transcription-addiction/"}],"term":[{"id":"nonmutational-epigenetic-reprogramming","kind":"term","name":"Hallmark (2022): non-mutational epigenetic reprogramming","route":"/terms/nonmutational-epigenetic-reprogramming/"},{"id":"hma","kind":"term","name":"Hypomethylating agents (azacitidine, decitabine)","route":"/terms/hma/"}],"trial":[{"id":"agile","kind":"trial","name":"AGILE","route":"/trials/agile/"},{"id":"augment-101","kind":"trial","name":"AUGMENT-101","route":"/trials/augment-101/"},{"id":"claridhy","kind":"trial","name":"ClarIDHy","route":"/trials/claridhy/"},{"id":"golseek-1","kind":"trial","name":"GOLSEEK-1","route":"/trials/golseek-1/"},{"id":"komet-001","kind":"trial","name":"KOMET-001","route":"/trials/komet-001/"},{"id":"mevpro-1","kind":"trial","name":"MEVPRO-1","route":"/trials/mevpro-1/"},{"id":"viale-a","kind":"trial","name":"VIALE-A","route":"/trials/viale-a/"}],"person":[{"id":"christopher-vakoc","kind":"person","name":"Christopher R. Vakoc","route":"/people/christopher-vakoc/"},{"id":"courtney-dinardo","kind":"person","name":"Courtney D. DiNardo","route":"/people/courtney-dinardo/"},{"id":"eytan-stein","kind":"person","name":"Eytan M. Stein","route":"/people/eytan-stein/"},{"id":"ghayas-issa","kind":"person","name":"Ghayas C. Issa","route":"/people/ghayas-issa/"},{"id":"ingo-mellinghoff","kind":"person","name":"Ingo K. Mellinghoff","route":"/people/ingo-mellinghoff/"},{"id":"pierre-fenaux","kind":"person","name":"Pierre Fenaux","route":"/people/pierre-fenaux/"},{"id":"stephen-baylin","kind":"person","name":"Stephen B. Baylin","route":"/people/stephen-baylin/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/"},{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"},{"id":"b-tumor-heterogeneity","kind":"bottleneck","name":"Tumour heterogeneity and clonal evolution","route":"/bottlenecks/b-tumor-heterogeneity/"}]}}