{"id":"epigenetics-roadmap","name":"Epigenetic therapy roadmap: loosening silenced genes → mutation-specific enzymes → editing the epigenome","route":"/roadmaps/epigenetics-roadmap/","eras":[{"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.","status":"historic","refs":[{"id":"stephen-baylin","kind":"person","name":"Stephen B. Baylin","route":"/people/stephen-baylin/","tldr":"Founder of cancer epigenetics, showing that abnormal DNA methylation silences tumour-suppressor genes and can be reversed by drugs."},{"id":"epigenetic-reprogramming","kind":"pathway","name":"Epigenetic reprogramming","route":"/pathways/epigenetic-reprogramming/","tldr":"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."},{"id":"azacitidine","kind":"drug","name":"Azacitidine","route":"/drugs/azacitidine/","status":"approved","tldr":"A gentle chemotherapy that switches silenced genes back on. With venetoclax it became the standard for older people with AML who cannot take intensive treatment."},{"id":"decitabine","kind":"drug","name":"Decitabine","route":"/drugs/decitabine/","status":"approved","tldr":"Decitabine (Dacogen) is an infusion that loosens the chemical silencing of genes in myelodysplastic syndromes and acute myeloid leukaemia, helping the bone marrow work again. An oral version combined with cedazuridine has its own record."},{"id":"hma","kind":"term","name":"Hypomethylating agents (azacitidine, decitabine)","route":"/terms/hma/","tldr":"Low-intensity chemotherapy that strips chemical 'off' switches (methyl groups) from DNA so silenced genes can be read again. The mainstay for older patients with AML and high-risk MDS, especially combined with venetoclax."},{"id":"pierre-fenaux","kind":"person","name":"Pierre Fenaux","route":"/people/pierre-fenaux/","tldr":"Led AZA-001, which showed azacitidine extends survival in high-risk MDS and made hypomethylating agents standard."},{"id":"vorinostat","kind":"drug","name":"Vorinostat","route":"/drugs/vorinostat/","status":"approved","tldr":"Vorinostat (Zolinza) was the first drug of its kind, a capsule that loosens the chemical packaging of DNA. It treats the skin disease of cutaneous T-cell lymphoma after two other treatments have failed."},{"id":"hdac","kind":"target","name":"Histone deacetylases (HDAC)","route":"/targets/hdac/","tldr":"Histone deacetylases tighten the packaging of DNA so that genes are switched off. Drugs that block them loosen the packaging and can wake up genes that make lymphoma cells stop growing or die."}],"trials":[],"papers":[]},{"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.","status":"historic","refs":[{"id":"romidepsin","kind":"drug","name":"Romidepsin","route":"/drugs/romidepsin/","status":"approved","tldr":"Romidepsin is an epigenetic drug for T-cell lymphomas of the skin and lymph nodes; its US lymph-node indication was withdrawn when a confirmatory trial failed."},{"id":"belinostat","kind":"drug","name":"Belinostat","route":"/drugs/belinostat/","status":"approved","tldr":"Belinostat is an HDAC inhibitor for relapsed peripheral T-cell lymphoma; about a quarter of patients respond, and it can be used in patients with low platelets."},{"id":"tucidinostat","kind":"drug","name":"Tucidinostat (chidamide)","route":"/drugs/tucidinostat/","status":"approved","tldr":"Chidamide, approved in 2014, was the first epigenetic cancer drug invented in China and the first oral drug of its kind anywhere, used for T-cell lymphoma and, with hormone therapy, for breast cancer."},{"id":"chipscreen","kind":"company","name":"Chipscreen Biosciences","route":"/companies/chipscreen/","tldr":"Chipscreen discovered chidamide (tucidinostat), the first original epigenetic cancer drug from China, approved in 2014 and later in Japan."},{"id":"panobinostat","kind":"drug","name":"Panobinostat","route":"/drugs/panobinostat/","status":"withdrawn","tldr":"An HDAC inhibitor for relapsed myeloma approved in 2015 and withdrawn in 2021 after its confirmatory trial was never completed."},{"id":"epigenetic-drugs","kind":"technology","name":"Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)","route":"/technologies/epigenetic-drugs/","status":"approved","tldr":"Drugs that change how genes are switched on and off without changing the DNA itself."}],"trials":[],"papers":[]},{"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.","status":"current","refs":[{"id":"ivosidenib","kind":"drug","name":"Ivosidenib","route":"/drugs/ivosidenib/","status":"approved","tldr":"The first drug to block a mutant metabolic enzyme in cancer. With azacitidine it tripled survival in IDH1-mutated AML that could not take intensive chemotherapy."},{"id":"enasidenib","kind":"drug","name":"Enasidenib","route":"/drugs/enasidenib/","status":"approved","tldr":"Enasidenib is the IDH2 counterpart of ivosidenib, approved in the US for relapsed disease but never approved in Europe after it failed to extend survival in a confirmatory trial."},{"id":"olutasidenib","kind":"drug","name":"Olutasidenib","route":"/drugs/olutasidenib/","status":"approved","tldr":"Olutasidenib is a second IDH1 inhibitor for relapsed AML, with a higher response rate in its pivotal cohort than ivosidenib had in its own."},{"id":"agile","kind":"trial","name":"AGILE","route":"/trials/agile/","status":"positive","tldr":"In IDH1-mutated AML, adding ivosidenib to azacitidine tripled survival, one of the largest effects ever seen in a randomised AML trial."},{"id":"claridhy","kind":"trial","name":"ClarIDHy","route":"/trials/claridhy/","status":"positive","tldr":"The first randomised trial of a targeted drug in bile duct cancer; it slowed the disease without shrinking it."},{"id":"idh","kind":"target","name":"IDH1 / IDH2","route":"/targets/idh/","tldr":"A metabolic enzyme whose mutant form produces a molecule that scrambles how genes are read; blocking it slows brain tumours and leukaemias."},{"id":"idh-2hg","kind":"pathway","name":"Mutant IDH / 2-hydroxyglutarate","route":"/pathways/idh-2hg/","tldr":"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."},{"id":"tazemetostat","kind":"drug","name":"Tazemetostat","route":"/drugs/tazemetostat/","status":"withdrawn","tldr":"Tazemetostat was the first EZH2 inhibitor, approved for epithelioid sarcoma and follicular lymphoma in 2020 and withdrawn worldwide in 2026 after secondary blood cancers."},{"id":"ezh2","kind":"target","name":"EZH2","route":"/targets/ezh2/","tldr":"EZH2 is an enzyme that silences genes. The first drug against it treated a rare sarcoma and some lymphomas until it was withdrawn in 2026 for causing second blood cancers."}],"trials":[{"id":"agile","name":"AGILE","route":"/trials/agile/","outcomes":[{"endpoint":"Event-free survival","primary":true,"arms":[{"name":"Ivosidenib + azacitidine","n":72},{"name":"Placebo + azacitidine","n":74}],"hr":0.33,"ci":[0.16,0.69],"p":"0.002","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2117344"},{"endpoint":"Overall survival (median)","unit":"months","arms":[{"name":"Ivosidenib + azacitidine","value":24},{"name":"Placebo + azacitidine","value":7.9}],"hr":0.44,"ci":[0.27,0.73],"source":"https://doi.org/10.1056/NEJMoa2117344"},{"endpoint":"Complete remission","unit":"%","arms":[{"name":"Ivosidenib + azacitidine","value":47},{"name":"Placebo + azacitidine","value":15}],"source":"https://doi.org/10.1056/NEJMoa2117344"}],"setting":"Newly diagnosed IDH1-mutated AML unfit for intensive chemotherapy: ivosidenib + azacitidine vs placebo + azacitidine","enrolled":146,"enrolledBasis":"registry"},{"id":"claridhy","name":"ClarIDHy","route":"/trials/claridhy/","outcomes":[{"endpoint":"Progression-free survival","primary":true,"unit":"months","arms":[{"name":"Ivosidenib","n":126,"value":2.7},{"name":"Placebo","n":61,"value":1.4}],"hr":0.37,"ci":[0.25,0.54],"p":"<0.0001","source":"https://doi.org/10.1016/S1470-2045(20)30157-1"},{"endpoint":"Overall survival (crossover-adjusted)","unit":"months","arms":[{"name":"Ivosidenib","value":10.3},{"name":"Placebo","value":7.5}],"hr":0.49,"source":"https://doi.org/10.1016/S1470-2045(20)30157-1"}],"setting":"Previously treated IDH1-mutant cholangiocarcinoma: ivosidenib vs placebo","enrolled":187,"enrolledBasis":"registry"}],"papers":[]},{"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.","status":"current","refs":[{"id":"viale-a","kind":"trial","name":"VIALE-A","route":"/trials/viale-a/","status":"positive","tldr":"The trial that gave older AML patients a real treatment: adding venetoclax to azacitidine doubled remission rates and extended survival."},{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/","status":"approved","tldr":"A pill that removes the survival shield from leukaemia cells, enabling chemotherapy-free, time-limited treatment for CLL."},{"id":"azacitidine","kind":"drug","name":"Azacitidine","route":"/drugs/azacitidine/","status":"approved","tldr":"A gentle chemotherapy that switches silenced genes back on. With venetoclax it became the standard for older people with AML who cannot take intensive treatment."},{"id":"decitabine-cedazuridine","kind":"drug","name":"Decitabine + cedazuridine (oral)","route":"/drugs/decitabine-cedazuridine/","status":"approved","tldr":"Oral decitabine-cedazuridine is a pill version of the hypomethylating chemotherapy that, since May 2026, lets older AML patients take their whole venetoclax regimen at home."},{"id":"courtney-dinardo","kind":"person","name":"Courtney D. DiNardo","route":"/people/courtney-dinardo/","tldr":"Led VIALE-A, which made venetoclax plus azacitidine the standard for older patients with acute myeloid leukaemia."},{"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/","tldr":"Adding the BCL-2 inhibitor venetoclax to azacitidine more than doubled remission rates and extended median survival from 9.6 to 14.7 months in unfit AML patients."}],"trials":[{"id":"viale-a","name":"VIALE-A","route":"/trials/viale-a/","outcomes":[{"endpoint":"Overall survival (median)","primary":true,"unit":"months","arms":[{"name":"Venetoclax + azacitidine","n":286,"value":14.7},{"name":"Placebo + azacitidine","n":145,"value":9.6}],"hr":0.66,"ci":[0.52,0.85],"p":"<0.001","source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2012971"},{"endpoint":"Complete remission","primary":true,"unit":"%","arms":[{"name":"Venetoclax + azacitidine","value":36.7},{"name":"Placebo + azacitidine","value":17.9}],"source":"https://doi.org/10.1056/NEJMoa2012971"},{"endpoint":"Composite CR (CR + CRi)","unit":"%","arms":[{"name":"Venetoclax + azacitidine","value":66.4},{"name":"Placebo + azacitidine","value":28.3}],"source":"https://doi.org/10.1056/NEJMoa2012971"}],"setting":"Newly diagnosed AML unfit for intensive chemotherapy: venetoclax + azacitidine vs placebo + azacitidine","enrolled":443,"enrolledBasis":"registry"}],"papers":[{"id":"paper-viale-a-venetoclax-azacitidine-nejm-2020","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/","journal":"New England Journal of Medicine","year":2020,"whatItMeans":"VIALE-A turned a palliative regimen into one that produces remission in two-thirds of older AML patients and is now the reference treatment for anyone not fit for intensive chemotherapy. It shifted the field towards lower-intensity targeted combinations and opened the door to adding FLT3, IDH and menin inhibitors to the backbone. Cure remains uncommon and most patients relapse within two years."}]},{"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.","status":"current","refs":[{"id":"revumenib","kind":"drug","name":"Revumenib","route":"/drugs/revumenib/","status":"approved","tldr":"Revumenib (Revuforj) is the first menin inhibitor (2024), for acute leukaemias with KMT2A rearrangements or NPM1 mutations."},{"id":"ziftomenib","kind":"drug","name":"Ziftomenib","route":"/drugs/ziftomenib/","status":"approved","tldr":"Ziftomenib is the second menin inhibitor for leukaemia, approved in November 2025 as a once-daily pill for relapsed NPM1-mutated AML."},{"id":"augment-101","kind":"trial","name":"AUGMENT-101","route":"/trials/augment-101/","status":"positive","tldr":"The trial that turned menin inhibition from an idea into the first approved drug for KMT2A-rearranged leukaemia."},{"id":"komet-001","kind":"trial","name":"KOMET-001","route":"/trials/komet-001/","status":"positive","tldr":"KOMET-001 was the registration trial for ziftomenib: a quarter of heavily pretreated patients with NPM1-mutated AML reached complete remission on a once-daily pill."},{"id":"menin","kind":"target","name":"Menin","route":"/targets/menin/","tldr":"A scaffold protein that certain leukaemias need to keep their genes switched on; the first drug against it was approved in 2024."},{"id":"menin-kmt2a","kind":"pathway","name":"Menin / KMT2A (HOXA9-MEIS1 axis)","route":"/pathways/menin-kmt2a/","tldr":"In some leukaemias a broken chromatin protein (KMT2A, once called MLL) or a mutant NPM1 keeps embryonic growth genes (HOXA9, MEIS1) switched on, so blood cells never mature. Both need a partner called menin to stay on the DNA. Menin inhibitors pull the plug and the cells mature; the first was approved in 2024."},{"id":"eytan-stein","kind":"person","name":"Eytan M. Stein","route":"/people/eytan-stein/","tldr":"Led the enasidenib and revumenib trials that brought IDH2 and menin inhibitors to acute leukaemia."},{"id":"ghayas-issa","kind":"person","name":"Ghayas C. Issa","route":"/people/ghayas-issa/","tldr":"First author of the revumenib trial that created the menin inhibitor class for acute leukaemia."},{"id":"vorasidenib","kind":"drug","name":"Vorasidenib","route":"/drugs/vorasidenib/","status":"approved","tldr":"The first targeted therapy for low-grade brain tumours, delaying the need for radiation and chemotherapy by years."},{"id":"ingo-mellinghoff","kind":"person","name":"Ingo K. Mellinghoff","route":"/people/ingo-mellinghoff/","tldr":"Led INDIGO, the trial that made vorasidenib the first targeted therapy for low-grade IDH-mutant glioma."},{"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/","tldr":"An oral drug that blocks the mutant IDH enzyme more than doubled the time before slow-growing IDH-mutant brain tumours progressed, letting patients postpone radiotherapy and chemotherapy for years."},{"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/","tldr":"Blocking menin, a scaffold protein the leukaemia depends on, produced remissions in heavily pretreated patients with KMT2A-rearranged or NPM1-mutated acute leukaemia."}],"trials":[{"id":"augment-101","name":"AUGMENT-101","route":"/trials/augment-101/","outcomes":[{"endpoint":"CR + CRh (KMT2Ar cohort)","primary":true,"unit":"%","arms":[{"name":"Revumenib","n":57,"value":22.8}],"source":"https://ascopubs.org/doi/10.1200/JCO.24.00826"},{"endpoint":"Overall response rate","unit":"%","arms":[{"name":"Revumenib","value":63.2}],"source":"https://doi.org/10.1200/JCO.24.00826"}],"setting":"Relapsed/refractory KMT2A-rearranged or NPM1-mutated acute leukaemia: revumenib monotherapy","enrolled":94,"enrolledNote":"ClinicalTrials.gov lists an estimated 447 participants for the whole phase 1/2 programme, which is still recruiting; the JCO 2024 KMT2A-rearranged analysis treated 94 patients between October 2021 and July 2023 (57 efficacy-evaluable).","enrolledBasis":"treated"},{"id":"komet-001","name":"KOMET-001","route":"/trials/komet-001/","outcomes":[{"endpoint":"Complete remission","primary":true,"unit":"%","arms":[{"name":"Ziftomenib","n":112,"value":23}],"source":"https://www.appliedclinicaltrialsonline.com/view/fda-approves-komzifti-npm1-mutated-aml-positive-komet-001-trial-data"},{"endpoint":"Overall response rate","unit":"%","arms":[{"name":"Ziftomenib","value":33}]},{"endpoint":"Overall survival (median)","unit":"months","arms":[{"name":"Ziftomenib","value":6.6}]}],"setting":"Relapsed/refractory NPM1-mutated AML: ziftomenib 600 mg daily monotherapy","enrolled":112,"enrolledNote":"ClinicalTrials.gov lists an estimated 263 participants for the phase 1/2 study; 112 is the FDA efficacy population at 600 mg quoted in the approval coverage, while the JCO 2025 phase 2 paper reports 92 patients treated between January 2023 and May 2024.","enrolledBasis":"treated"}],"papers":[{"id":"paper-indigo-nejm-2023","name":"INDIGO: vorasidenib, the first targeted drug for IDH-mutant low-grade glioma","route":"/key-papers/paper-indigo-nejm-2023/","journal":"New England Journal of Medicine","year":2023,"whatItMeans":"Young adults with a grade 2 IDH-mutant glioma who have had surgery can now take a daily tablet that slows or reverses tumour growth and defers radiotherapy and chemotherapy, both of which carry long-term cognitive costs, by years. It confirms that the IDH mutation is a driver that can be targeted, not just a marker. Whether it improves survival or cognition over the long term, and whether it helps in higher-grade or previously treated tumours, is unknown."},{"id":"paper-augment-101-revumenib-menin-nature-2023","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/","journal":"Nature","year":2023,"whatItMeans":"Revumenib proved that a transcriptional dependency, rather than a kinase, can be drugged in leukaemia, opening treatment for two genetic subgroups that together cover roughly a third of AML plus most infant ALL. It is now approved and is being combined with venetoclax-azacitidine and intensive chemotherapy in front-line trials. Single-agent remissions are often short without transplant."}]},{"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.","status":"emerging","refs":[{"id":"mevrometostat","kind":"drug","name":"Mevrometostat","route":"/drugs/mevrometostat/","status":"phase-3","tldr":"An epigenetic drug that may re-sensitise prostate cancer to hormone therapy, in three phase 3 trials with enzalutamide."},{"id":"mevpro-1","kind":"trial","name":"MEVPRO-1","route":"/trials/mevpro-1/","status":"active","tldr":"MEVPRO-1 is the phase 3 trial of the first EZH2 inhibitor combination in prostate cancer."},{"id":"prmt5-mtap","kind":"target","name":"PRMT5 (MTAP-deleted cancers)","route":"/targets/prmt5-mtap/","tldr":"An enzyme that cancers lacking the MTAP gene (about 10-15% of all tumours) depend on more than normal cells do; new inhibitors designed to exploit that difference are in late trials."},{"id":"golcadomide","kind":"drug","name":"Golcadomide","route":"/drugs/golcadomide/","status":"phase-3","tldr":"Golcadomide is a next-generation lenalidomide-like pill that degrades two lymphoma transcription factors far more potently, now in phase 3 with R-CHOP."},{"id":"golseek-1","kind":"trial","name":"GOLSEEK-1","route":"/trials/golseek-1/","status":"active","tldr":"GOLSEEK-1 is a recruiting phase 3 that tests whether adding golcadomide, an oral cereblon-modulating degrader, to R-CHOP raises cure rates in untreated high-risk large B-cell lymphoma. It builds on high complete response rates in phase 1b, and readout is expected in 2027 to 2028."},{"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/","tldr":"Some sarcomas in children are caused by two genes fused into one abnormal protein. That protein is the whole disease, but no drug binds it. Destroying it instead of blocking it could work."},{"id":"swi-snf-chromatin","kind":"pathway","name":"SWI/SNF chromatin remodelling","route":"/pathways/swi-snf-chromatin/","tldr":"A machine that opens and closes DNA so genes can be read. One in five cancers has a broken part (ARID1A, SMARCA4, PBRM1), and losing one part often creates a dependence on its twin, which is the basis for new synthetic-lethal drugs."},{"id":"k36-therapeutics","kind":"company","name":"K36 Therapeutics","route":"/companies/k36-therapeutics/","tldr":"K36 Therapeutics makes pills that block an enzyme called NSD2 (also known as MMSET), which is overactive in about one in five multiple myeloma cases because of a chromosome swap. It is also testing the approach in prostate cancer."},{"id":"morphosys","kind":"company","name":"MorphoSys (Novartis)","route":"/companies/morphosys/","status":"historic","tldr":"German antibody company that acquired Constellation's BET inhibitor pelabresib and was itself bought by Novartis in 2024."},{"id":"eprenetapopt","kind":"drug","name":"Eprenetapopt","route":"/drugs/eprenetapopt/","status":"negative","tldr":"Eprenetapopt (APR-246) was a drug meant to refold mutant p53, the most common broken protein in cancer. Its phase 3 in blood cancer failed in 2020."},{"id":"transcription-addiction","kind":"pathway","name":"Transcriptional machinery & addiction","route":"/pathways/transcription-addiction/","tldr":"Cancer cells run a few genes (MYC, their lineage factors, their fusion oncogenes) at extreme volume from giant control regions called super-enhancers. The amplifiers, BRD4, CDK7, CDK9 and Mediator, are the same in every cell, but cancers are unusually dependent on them, and that dependence is druggable."},{"id":"myc","kind":"pathway","name":"MYC","route":"/pathways/myc/","tldr":"MYC is the most commonly amplified cancer gene, a master switch that turns on thousands of growth genes. It has no pocket for a conventional drug, so it remained 'undruggable' for 40 years; the first direct MYC drugs finally entered trials in the 2020s."},{"id":"christopher-vakoc","kind":"person","name":"Christopher R. Vakoc","route":"/people/christopher-vakoc/","tldr":"Found that leukaemias depend on the chromatin reader BRD4, launching BET inhibitors, and mapped transcriptional addictions in sarcoma."}],"trials":[],"papers":[]},{"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.","status":"speculative","refs":[{"id":"epigenetic-editing","kind":"technology","name":"Epigenetic editing (durable gene silencing)","route":"/technologies/epigenetic-editing/","status":"concept","tldr":"Switching a gene off for good without changing the DNA sequence, by writing chemical marks onto it."},{"id":"nonmutational-epigenetic-reprogramming","kind":"term","name":"Hallmark (2022): non-mutational epigenetic reprogramming","route":"/terms/nonmutational-epigenetic-reprogramming/","tldr":"Cancers can change behaviour, including becoming drug-tolerant, without any new mutation, by rewriting the chemical tags that control which genes are read."},{"id":"arpeggio-bio","kind":"company","name":"Arpeggio Bio","route":"/companies/arpeggio-bio/","tldr":"Arpeggio Bio uses AI on large RNA-sequencing datasets to find drugs against transcription factors, the hard-to-hit proteins that switch cancer genes on, with a first programme in immunotherapy-resistant melanoma."},{"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/","tldr":"The third hallmarks paper proposed two new hallmarks (unlocking phenotypic plasticity, senescent cells) and two new enabling characteristics (non-mutational epigenetic reprogramming, polymorphic microbiomes), bringing the framework to fourteen elements."},{"id":"frontier-2035","kind":"roadmap","name":"Radical oncology: what could change the war by 2035","route":"/roadmaps/frontier-2035/","tldr":"Radical oncology is a horizon map of the wilder ideas in cancer, sorted by how close they are to mattering, with the reason each one might never arrive."}],"trials":[],"papers":[{"id":"paper-hallmarks-new-dimensions-cancer-discov-2022","name":"Hallmarks of Cancer 2022: adding phenotypic plasticity, epigenetic reprogramming, microbiomes and senescent cells","route":"/key-papers/paper-hallmarks-new-dimensions-cancer-discov-2022/","journal":"Cancer Discovery","year":2022,"whatItMeans":"Cancer is now understood to change its identity and behaviour without new mutations, to be shaped by bacteria inside and around it, and to be helped along by ageing cells. This explains why some tumours escape targeted drugs by changing cell type and why gut bacteria affect immunotherapy response."}]},{"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.","status":"current","refs":[{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/","tldr":"The proteins that drive most cancers, such as MYC, mutant p53 and most RAS variants, still have no good drug."},{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/","tldr":"Nearly every targeted therapy stops working within months to a few years as the tumour adapts."},{"id":"b-tumor-heterogeneity","kind":"bottleneck","name":"Tumour heterogeneity and clonal evolution","route":"/bottlenecks/b-tumor-heterogeneity/","tldr":"Every tumour is a population of genetically distinct clones: in multi-region sequencing of kidney tumours, roughly two thirds of mutations were missing from at least one region. Treatment kills the dominant clones and leaves resistant minor clones to grow back, yet a single diagnostic biopsy is still treated as the whole disease."},{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/","tldr":"Tests that decide who gets a drug are often not validated prospectively and are measured differently in every lab."},{"id":"protac-degrader","kind":"technology","name":"PROTACs & molecular glues (targeted protein degradation)","route":"/technologies/protac-degrader/","status":"approved","tldr":"Instead of blocking a protein, these drugs tag it for the cell's own garbage disposal, removing it entirely."},{"id":"methylation-profiling","kind":"technology","name":"DNA methylation profiling","route":"/technologies/methylation-profiling/","status":"established","tldr":"Reading chemical tags on DNA that reveal a cell's identity, used to classify brain tumours and to detect cancer in blood."}],"trials":[],"papers":[]}],"watch":[]}