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

Founder of cancer epigenetics, showing that abnormal DNA methylation silences tumour-suppressor genes and can be reversed by 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.

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.

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.

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.

Led AZA-001, which showed azacitidine extends survival in high-risk MDS and made hypomethylating agents standard.

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.

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.

Romidepsin is an epigenetic drug for T-cell lymphomas of the skin and lymph nodes; its US lymph-node indication was withdrawn when a confirmatory trial failed.

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.

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.

Chipscreen discovered chidamide (tucidinostat), the first original epigenetic cancer drug from China, approved in 2014 and later in Japan.

An HDAC inhibitor for relapsed myeloma approved in 2015 and withdrawn in 2021 after its confirmatory trial was never completed.

Drugs that change how genes are switched on and off without changing the DNA itself.

Ivosidenib is a pill that blocks the mutant IDH1 enzyme, approved in bile duct cancer and in leukaemia.

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.

Olutasidenib is a second IDH1 inhibitor for relapsed AML, with a higher response rate in its pivotal cohort than ivosidenib had in its own.

In IDH1-mutated AML, adding ivosidenib to azacitidine tripled survival, one of the largest effects ever seen in a randomised AML trial.

The first randomised trial of a targeted drug in bile duct cancer; it slowed the disease without shrinking it.

A metabolic enzyme whose mutant form produces a molecule that scrambles how genes are read; blocking it slows brain tumours and leukaemias.

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.

Tazemetostat was the first EZH2 inhibitor, approved for epithelioid sarcoma and follicular lymphoma in 2020 and withdrawn worldwide in 2026 after secondary blood cancers.

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.

The trial that gave older AML patients a real treatment: adding venetoclax to azacitidine doubled remission rates and extended survival.

A pill that removes the survival shield from leukaemia cells, enabling chemotherapy-free, time-limited treatment for CLL.

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.

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.

Led VIALE-A, which made venetoclax plus azacitidine the standard for older patients with acute myeloid leukaemia.

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.

Revumenib (Revuforj) is the first menin inhibitor (2024), for acute leukaemias with KMT2A rearrangements or NPM1 mutations.

Ziftomenib is the second menin inhibitor for leukaemia, approved in November 2025 as a once-daily pill for relapsed NPM1-mutated AML.

The trial that turned menin inhibition from an idea into the first approved drug for KMT2A-rearranged leukaemia.

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.

A scaffold protein that certain leukaemias need to keep their genes switched on; the first drug against it was approved in 2024.

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.

Led the enasidenib and revumenib trials that brought IDH2 and menin inhibitors to acute leukaemia.

First author of the revumenib trial that created the menin inhibitor class for acute leukaemia.

The first targeted therapy for low-grade brain tumours, delaying the need for radiation and chemotherapy by years.

Led INDIGO, the trial that made vorasidenib the first targeted therapy for low-grade IDH-mutant glioma.

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.

Blocking menin, a scaffold protein the leukaemia depends on, produced remissions in heavily pretreated patients with KMT2A-rearranged or NPM1-mutated acute leukaemia.

An epigenetic drug that may re-sensitise prostate cancer to hormone therapy, in three phase 3 trials with enzalutamide.

MEVPRO-1 is the phase 3 trial of the first EZH2 inhibitor combination in prostate cancer.

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.

Golcadomide is a next-generation lenalidomide-like pill that degrades two lymphoma transcription factors far more potently, now in phase 3 with R-CHOP.

Tests whether a potent oral degrader added to R-CHOP raises cure rates in high-risk disease.

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.

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.

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.

German antibody company that acquired Constellation's BET inhibitor pelabresib and was itself bought by Novartis in 2024.

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.

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.

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.

Found that leukaemias depend on the chromatin reader BRD4, launching BET inhibitors, and mapped transcriptional addictions in sarcoma.

Switching a gene off for good without changing the DNA sequence, by writing chemical marks onto it.

Cancers can change behaviour, including becoming drug-tolerant, without any new mutation, by rewriting the chemical tags that control which genes are read.

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.

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.

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.

The proteins that drive most cancers, such as MYC, mutant p53 and most RAS variants, still have no good drug.

Nearly every targeted therapy stops working within months to a few years as the tumour adapts.

A tumour is many tumours. Treatments that kill most cells leave the rest to grow back, changed.

Tests that decide who gets a drug are often not validated prospectively and are measured differently in every lab.

Instead of blocking a protein, these drugs tag it for the cell's own garbage disposal, removing it entirely.

Reading chemical tags on DNA that reveal a cell's identity, used to classify brain tumours and to detect cancer in blood.