{"entity":{"id":"nut-carcinoma","kind":"cancer","name":"NUT carcinoma (midline carcinoma with NUTM1 rearrangement)","aka":["NUT midline carcinoma","Midline tract carcinoma with NUT gene changes","NMC"],"tldr":"NUT carcinoma is a fast-growing cancer of the midline of the body driven by a single fused gene, BRD4-NUTM1, that locks cells in an immature state. Chemotherapy and surgery rarely control it for long, but drugs that block the BET proteins the fusion depends on have produced responses and are the focus of trials.","summary":"NUT carcinoma is a poorly differentiated squamous carcinoma defined by rearrangement of NUTM1 (nuclear protein in testis), most often fused to BRD4 (about 70 percent), otherwise BRD3, NSD3 or ZNF532. The fusion protein tethers NUT's histone acetyltransferase-recruiting domain to BET bromodomains, creating megadomains of hyperacetylated chromatin that drive MYC and SOX2 expression and block squamous differentiation. It was first recognised in the mediastinum of children and young adults but occurs at any age and in the sinonasal tract, lung, and other sites; diagnosis requires NUT immunohistochemistry (highly specific) or fusion testing, and many cases were historically misdiagnosed as undifferentiated carcinoma or sarcoma.\n\nThe disease is among the most aggressive human cancers. Multimodality treatment (surgery, radiotherapy and ifosfamide- or platinum-based chemotherapy, Ewing-type regimens) achieves control in a minority, mostly those with localised disease amenable to complete resection and radiotherapy. The International NUT Carcinoma Registry (Brigham and Women's Hospital) has pooled outcomes and shown that initial resection or radiotherapy is associated with longer survival, and that non-BRD4 fusions have a somewhat better course.\n\nMechanistically the disease is an ideal test of BET inhibition: BRD4-NUTM1 requires bromodomain binding to chromatin. BET inhibitors (molibresib/GSK525762, birabresib/OTX015, ZEN-3694, NUV-868) have produced objective responses and disease stabilisation in NUT carcinoma cohorts of phase 1 and 2 trials, with thrombocytopenia as the dose-limiting toxicity; combination with chemotherapy, CDK9 or HDAC inhibitors, and next-generation BET degraders are the main directions. Rapid, accurate diagnosis is the first intervention that changes outcome.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/NUT_midline_carcinoma","links":[{"label":"NCI PDQ: childhood midline tract carcinoma with NUT gene changes","url":"https://www.cancer.gov/types/midline/patient-child-midline-tract-carcinoma-treatment-pdq"},{"label":"Filippakopoulos 2010: BET inhibition in NUT carcinoma (Nature)","url":"https://doi.org/10.1038/nature09504"}],"tags":["nci-coverage","rare","head-and-neck","paediatric"],"related":[],"cancers":[],"sections":[],"technologies":["epigenetic-drugs","cytotoxic-chemotherapy","imrt-igrt"],"targets":[],"drugs":["ifosfamide","cisplatin","etoposide"],"companies":[],"institutions":["dana-farber"],"pathways":["transcription-addiction","epigenetic-reprogramming","myc"],"terms":["gene-fusion","rare-cancers"],"trials":[],"people":[],"bottlenecks":["b-rare-cancers","b-undruggable-targets"],"keyPapers":["paper-filippakopoulos-nature"],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"Very rare and under-recognised; arises at any age with a median in the twenties, most often in the head, neck and thorax.","subtypes":["BRD4-NUTM1 (most common)","BRD3-NUTM1","NSD3-NUTM1","Other NUTM1 partners (ZNF532, ZNF592)"],"biomarkers":["NUT immunohistochemistry (C52 antibody, nuclear speckled)","NUTM1 fusion by FISH or RNA sequencing","Fusion partner (non-BRD4 partners associated with longer survival in the registry)","Site (thoracic vs non-thoracic)"],"standardOfCare":[{"setting":"Localised","approach":"Multimodality: complete resection where feasible, radiotherapy, and intensive chemotherapy (ifosfamide-based or platinum-based, often Ewing-type regimens); early referral to a centre with NUT carcinoma experience.","refs":["ifosfamide","cisplatin","imrt-igrt"],"guideline":{"version":"NCI PDQ: childhood midline tract carcinoma with NUT gene changes; International NUT Carcinoma Registry","url":"https://www.cancer.gov/types/midline/patient-child-midline-tract-carcinoma-treatment-pdq"}},{"setting":"Advanced or relapsed","approach":"Clinical trial of a BET inhibitor (ZEN-3694, NUV-868, molibresib) alone or with chemotherapy; palliative chemotherapy and radiotherapy.","refs":["epigenetic-drugs"]}],"stateOfArt":["A single oncogenic fusion with a druggable domain: NUT carcinoma is the founding indication for BET bromodomain inhibitors.","NUT immunohistochemistry has made diagnosis fast and cheap, and is now recommended for any poorly differentiated midline carcinoma, particularly in young patients.","Registry data show that complete resection and radiotherapy of localised disease produce long-term survivors, so long-term survival is achievable.","BET inhibitors have shown objective responses, but durability is limited; degraders and combinations are the next step."],"history":[{"year":1991,"title":"First reports of aggressive midline carcinoma with t(15;19) in children","refs":[]},{"year":2003,"title":"BRD4-NUT fusion cloned","note":"French and colleagues identify the fusion gene.","refs":[]},{"year":2009,"title":"NUT immunohistochemistry validated","note":"Haack and colleagues: highly specific antibody enables diagnosis.","refs":[]},{"year":2010,"title":"BET inhibitor JQ1 induces differentiation of NUT carcinoma cells","note":"Filippakopoulos and colleagues, Nature: proof of concept for BET inhibition.","refs":[]},{"year":2016,"title":"First BET inhibitor responses in patients","note":"Birabresib (OTX015) and molibresib phase 1 cohorts.","refs":["epigenetic-drugs"]},{"year":2021,"title":"International NUT Carcinoma Registry outcomes","note":"Chau and colleagues, JCO: fusion partner and initial treatment predict survival.","refs":[]}],"pipeline":["zen-3694","zen-3694-platinum-nut","zen-3694-abemaciclib-nut","cemiplimab-nut","epigenetic-drugs","checkpoint-inhibitor"],"openProblems":["Misdiagnosis and delay: NUT immunohistochemistry should be routine in poorly differentiated midline tumours.","BET inhibitor responses are short: degraders, CDK9 and HDAC combinations, and chemotherapy combinations are in trials.","Thrombocytopenia limits BET inhibitor dosing.","No randomised trials exist; the registry is the evidence base."]},"route":"/cancers/nut-carcinoma/","neighbours":{"technology":[{"id":"cytotoxic-chemotherapy","kind":"technology","name":"Cytotoxic chemotherapy","route":"/technologies/cytotoxic-chemotherapy/"},{"id":"epigenetic-drugs","kind":"technology","name":"Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)","route":"/technologies/epigenetic-drugs/"},{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"imrt-igrt","kind":"technology","name":"IMRT / IGRT (modern external beam)","route":"/technologies/imrt-igrt/"}],"drug":[{"id":"cisplatin","kind":"drug","name":"Cisplatin","route":"/drugs/cisplatin/"},{"id":"etoposide","kind":"drug","name":"Etoposide","route":"/drugs/etoposide/"},{"id":"ifosfamide","kind":"drug","name":"Ifosfamide","route":"/drugs/ifosfamide/"},{"id":"zen-3694","kind":"drug","name":"ZEN-3694","route":"/drugs/zen-3694/"}],"institution":[{"id":"dana-farber","kind":"institution","name":"Dana-Farber Brigham Cancer Center","route":"/institutions/dana-farber/"}],"pathway":[{"id":"epigenetic-reprogramming","kind":"pathway","name":"Epigenetic reprogramming","route":"/pathways/epigenetic-reprogramming/"},{"id":"myc","kind":"pathway","name":"MYC","route":"/pathways/myc/"},{"id":"transcription-addiction","kind":"pathway","name":"Transcriptional machinery & addiction","route":"/pathways/transcription-addiction/"}],"term":[{"id":"gene-fusion","kind":"term","name":"Gene fusion","route":"/terms/gene-fusion/"},{"id":"rare-cancers","kind":"term","name":"Rare cancers","route":"/terms/rare-cancers/"}],"bottleneck":[{"id":"b-rare-cancers","kind":"bottleneck","name":"Rare and paediatric cancers without markets","route":"/bottlenecks/b-rare-cancers/"},{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"}],"paper":[{"id":"paper-filippakopoulos-nature","kind":"paper","name":"Selective inhibition of BET bromodomains","route":"/key-papers/paper-filippakopoulos-nature/"}],"trial":[{"id":"cemiplimab-nut","kind":"trial","name":"Cemiplimab in metastatic or unresectable NUT carcinoma (Northwestern pilot)","route":"/trials/cemiplimab-nut/"},{"id":"zen-3694-abemaciclib-nut","kind":"trial","name":"ZEN-3694 with abemaciclib in NUT carcinoma, breast cancer and other solid tumours (NCI phase 1)","route":"/trials/zen-3694-abemaciclib-nut/"},{"id":"zen-3694-platinum-nut","kind":"trial","name":"ZEN-3694 with platinum chemotherapy in NUT carcinoma (NCI phase 1/2)","route":"/trials/zen-3694-platinum-nut/"}],"cancer":[{"id":"esthesioneuroblastoma","kind":"cancer","name":"Esthesioneuroblastoma (olfactory neuroblastoma)","route":"/cancers/esthesioneuroblastoma/"},{"id":"rare-childhood-cancers","kind":"cancer","name":"Rare cancers of childhood (NCI PDQ umbrella)","route":"/cancers/rare-childhood-cancers/"},{"id":"sinonasal-undifferentiated-carcinoma","kind":"cancer","name":"Sinonasal undifferentiated carcinoma (SNUC) and SWI/SNF-deficient sinonasal carcinoma","route":"/cancers/sinonasal-undifferentiated-carcinoma/"}],"target":[{"id":"brd4","kind":"target","name":"BRD4","route":"/targets/brd4/"}]}}