RARE DISEASE
NUT midline carcinoma
NUT midline carcinoma
NUT midline carcinoma
Synonyms: NMC
Synonyms: NMC
Synonyms: NMC
Drug discovery
4
drugs
With orphan designations
Overview
NUT midline carcinoma (NMC) is a rare, genetically driven cancer defined by NUTM1 gene rearrangements (most commonly BRD4-NUT fusions) [4][14]. This aggressive malignancy typically arises in midline structures (head/neck, thorax) and presents as rapidly enlarging masses [1][7][16]. Diagnosed across all ages (median 20s), it exhibits dismal prognosis with median overall survival <1 year despite multimodal therapy [1][17][19].
Categories: rare neoplastic diseases
Research Papers
177 drug discovery papers about NUT midline carcinoma, with 1 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
177 drug discovery papers about NUT midline carcinoma, with 1 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-05-01 | Molecular reclassification of tracheoesophageal squamous cell carcinoma to BRD4–NUTM1–rearranged NUT midline carcinoma with early osseous metastases: A rare case highlighting the importance of molecular profiling
Nuclear protein in testis (NUT) carcinoma is a rare and highly aggressive malignancy characterized by rearrangement of the NUT midline carcinoma family member 1 (NUTM1) gene, most commonly involving a bromodomain-containing protein 4 (BRD4)–NUTM1 fusion, and is frequently underdiagnosed due to its histologic resemblance to poorly differentiated squamous cell carcinoma. We report a 41-year-old male who presented with cough and respiratory distress requiring airway stabilization and tracheobronchial stenting. Initial biopsy suggested poorly differentiated nonkeratinizing squamous cell carcinoma in the tracheoesophageal groove, and the patient received platinum-based chemotherapy followed by definitive chemoradiation, achieving a partial locoregional metabolic response. However, within 2 months, he developed early skeletal metastases confirmed on positron emission tomography/computed tomography and magnetic resonance imaging. Comprehensive molecular profiling subsequently identified a BRD4–NUTM1 fusion, leading to molecular reclassification as NUT carcinoma. The tumor demonstrated low Programmed Death-Ligand 1 (PD-L1) expression, low tumor mutational burden, and microsatellite stability. The patient was enrolled in a clinical trial evaluating bromodomain and extra-terminal domain inhibitors/BRD4 degraders. This case highlights the aggressive clinical course, diagnostic challenges, and the critical role of molecular profiling in accurately identifying NUT carcinoma and guiding targeted therapeutic strategies.
2026-04-29 | IRS4 is a PI3K-activating cancer dependency up-regulated through DNA rearrangements or epigenetic mechanisms in multiple solid tumors.
Cancer therapeutics frequently fail in clinical trials because of poor therapeutic index (efficacy-to-toxicity ratio). We systematically identified targets likely to have a good therapeutic index, revealing insulin receptor substrate 4 (IRS4) as a dependency in IRS4-expressing cancers. Pan-cancer analysis of pediatric-enriched cancers revealed IRS4 expression consistent with dependency in 68% of choroid plexus, 37% of malignant rhabdoid, 31% of NUT midline, and 5% of osteosarcomas, while in adult cancers, it was expressed in 8% of uterine leiomyosarcomas and 1 to 2% of lung squamous, stomach, and breast carcinomas. IRS4 expression in adult tumors was associated with enhancer hijacking rearrangements, including recurrent GATA3-IRS4 and ANKRD30A-IRS4 in breast cancer, while rhabdoid and NUT midline cancers expressed IRS4 epigenetically. IRS4 fueled cancer dependency through PI3K-Akt activation, and domain analysis revealed the PH and PTB domains, which have a predicted drug pocket, to be dispensable, suggesting degradation-based modalities. These data reveal IRS4 as a target in IRS4-expressing cancers and suggest inhibitory approaches.
2026-02-27 | Assessing the Tumor Immune Microenvironment of Sinonasal Nut Carcinoma
Background: NUT carcinoma is a highly aggressive cancer defined by rearrangements of the NUT midline carcinoma family member 1 gene. Despite aggressive treatment, patients have a median survival of only seven months. Currently, there is no standard treatment for NUT carcinoma, highlighting the need for new experimental models and improved treatment strategies. In previous research, we established and characterized two novel sinonasal NUT carcinoma cell lines from a surgical specimen. To gain a deeper understanding of the disease, we conducted a multiplex immunofluorescence study on the surgical specimen from which these cell lines were derived. Materials and Methods: A formalin-fixed, paraffin-embedded surgical specimen from a 28-year-old man who was diagnosed with T4bN0M0 sinonasal NUT carcinoma was used in this study. The patient underwent two cycles of induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil at another institution, followed by surgical resection at the University of Texas MD Anderson Cancer Center. Opal 7-color multiplex immunofluorescence was performed on the surgical specimen, using antibodies for pan-cytokeratin (CK, clone 80), CD3, CD8, PD-L1, CD68, CD56/NCAM (an NK cell marker), and DAPI. Tissue identification, marker detection, and data extraction were conducted using QuPath (version 0.5.1). Tumor cells with low CK expression were categorized as 'CK low ' cells, and their proportion within the tumor was calculated as CK low / (CK low + CK + ) x 100. Results: Fifty-four percent of the tumor cells were classified as CK low , indicating heterogeneity within this tumor sample. CD8 + tumor-infiltrating lymphocytes were present at only 0.14%, suggesting that this specimen exhibits a less immunogenic 'cold' tumor profile. The percentage of PD-L1-positive tumor cells, which is associated with a better response to immunotherapy in various tumor types, was less than 0.2%. Furthermore, the percentage of CD68 + PD-L1 + macrophages, another indicator for response to certain types of immunotherapies, was found to be less than 5%. Conclusion: The sample of sinonasal NUT carcinoma that we analyzed exhibited heterogeneous cytokeratin expression and low immunogenic characteristics. Given that NUT carcinoma is primarily driven by a single fusion oncoprotein, it has a low tumor mutational burden, which may align with these findings. Since conventional treatments for NUT carcinoma, such as chemotherapy and radiation therapy, have shown very limited success, it is essential to develop strategies to address the tumor immune microenvironment and to incorporate immunotherapy and potential new targetable therapies effectively. We plan to create an advanced panel with additional markers and include more tumor samples to further investigate the biology of sinonasal NUT carcinoma in our future studies. Publication History Article published online: 27 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2026-01-28 | NUTM1-rearranged sarcoma arising in the descending colon presenting as a submucosal mass: a case report
Abstract Purpose NUT midline carcinoma family number 1 ( NUTM1) -rearranged sarcoma is extremely rare and characterized by NUTM1 gene rearrangement with variable morphological features. The gastrointestinal tract is one of the most common sites. These sarcomas showing similar histopathological findings have yielded poor clinical outcomes. Case presentation A healthy 52-year-old Japanese man presented with a solitary, localized submucosal mass, 3 cm in size, in the descending colon. Microscopically, the sarcoma comprised sheet-like proliferation of plump epithelioid/rhabdoid cells, fibrosarcoma-like spindle cells showing an intersecting fascicular pattern, and neoplastic cell nests in hyalinized stroma. Immunohistochemistry (IHC) revealed that sarcoma cells were diffusely positive for NUT. Fluorescence in situ hybridization (FISH) confirmed NUTM1 gene rearrangement. Recurrences in the retroperitoneum at 9 and 21 months after initial surgery were surgically excised. The histopathological features and the results of IHC and FISH for the sarcoma coincided with those of previously reported NUTM1 -rearranged sarcoma occurring in the colon. The sarcoma recurred three times within a short time after the initial surgery. Therefore, the behavioral aggressiveness and site in which the sarcoma arose were also consistent with those of NUTM1 -rearranged sarcoma in the colon. Of note, these recurrent sarcomas comprised only a plump epithelioid/rhabdoid cell component. Conclusion We reported here an unusual sarcoma with unexpected poor outcomes. Our case may provide additional useful information regarding this extremely rare sarcoma of colonic submucosal origin.
2026-01-28 | NUT carcinoma of the cheek managed with chemotherapy and surgical resection.
NUT(Nuclear Protein in Testes) carcinoma is a rare and aggressive malignancy characterised by rearrangements of the NUTM1 gene, primarily affecting midline structures in children and adults. We report a middle childhood male who presented with a left cheek swelling initially noticed 2 months earlier, surgically resected 1 month ago and recurred over the past week. Histopathology revealed a poorly differentiated neoplasm, with immunohistochemistry showing diffuse CK5/6, P63, P40 expression, intact SMARCA4, P16 negativity and speckled NUT nuclear staining confirming NUT carcinoma. Imaging demonstrated local extension with small-volume nodal metastases. He was treated with nine cycles of VDC-IE(vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide) chemotherapy given at 3-week intervals, complicated by transient iron deficiency anaemia, followed by surgical excision with neck dissection and fibular flap reconstruction. Post-treatment positron emission tomography scan showed no metabolically active disease. Maintenance therapy with the histone deacetylase inhibitor vorinostat was initiated. This case highlights the importance of early recognition, multimodal therapy and emerging targeted treatment in improving outcomes for NUT carcinoma.
2026-05-01 | Molecular reclassification of tracheoesophageal squamous cell carcinoma to BRD4–NUTM1–rearranged NUT midline carcinoma with early osseous metastases: A rare case highlighting the importance of molecular profiling
Nuclear protein in testis (NUT) carcinoma is a rare and highly aggressive malignancy characterized by rearrangement of the NUT midline carcinoma family member 1 (NUTM1) gene, most commonly involving a bromodomain-containing protein 4 (BRD4)–NUTM1 fusion, and is frequently underdiagnosed due to its histologic resemblance to poorly differentiated squamous cell carcinoma. We report a 41-year-old male who presented with cough and respiratory distress requiring airway stabilization and tracheobronchial stenting. Initial biopsy suggested poorly differentiated nonkeratinizing squamous cell carcinoma in the tracheoesophageal groove, and the patient received platinum-based chemotherapy followed by definitive chemoradiation, achieving a partial locoregional metabolic response. However, within 2 months, he developed early skeletal metastases confirmed on positron emission tomography/computed tomography and magnetic resonance imaging. Comprehensive molecular profiling subsequently identified a BRD4–NUTM1 fusion, leading to molecular reclassification as NUT carcinoma. The tumor demonstrated low Programmed Death-Ligand 1 (PD-L1) expression, low tumor mutational burden, and microsatellite stability. The patient was enrolled in a clinical trial evaluating bromodomain and extra-terminal domain inhibitors/BRD4 degraders. This case highlights the aggressive clinical course, diagnostic challenges, and the critical role of molecular profiling in accurately identifying NUT carcinoma and guiding targeted therapeutic strategies.
2026-04-29 | IRS4 is a PI3K-activating cancer dependency up-regulated through DNA rearrangements or epigenetic mechanisms in multiple solid tumors.
Cancer therapeutics frequently fail in clinical trials because of poor therapeutic index (efficacy-to-toxicity ratio). We systematically identified targets likely to have a good therapeutic index, revealing insulin receptor substrate 4 (IRS4) as a dependency in IRS4-expressing cancers. Pan-cancer analysis of pediatric-enriched cancers revealed IRS4 expression consistent with dependency in 68% of choroid plexus, 37% of malignant rhabdoid, 31% of NUT midline, and 5% of osteosarcomas, while in adult cancers, it was expressed in 8% of uterine leiomyosarcomas and 1 to 2% of lung squamous, stomach, and breast carcinomas. IRS4 expression in adult tumors was associated with enhancer hijacking rearrangements, including recurrent GATA3-IRS4 and ANKRD30A-IRS4 in breast cancer, while rhabdoid and NUT midline cancers expressed IRS4 epigenetically. IRS4 fueled cancer dependency through PI3K-Akt activation, and domain analysis revealed the PH and PTB domains, which have a predicted drug pocket, to be dispensable, suggesting degradation-based modalities. These data reveal IRS4 as a target in IRS4-expressing cancers and suggest inhibitory approaches.
2026-02-27 | Assessing the Tumor Immune Microenvironment of Sinonasal Nut Carcinoma
Background: NUT carcinoma is a highly aggressive cancer defined by rearrangements of the NUT midline carcinoma family member 1 gene. Despite aggressive treatment, patients have a median survival of only seven months. Currently, there is no standard treatment for NUT carcinoma, highlighting the need for new experimental models and improved treatment strategies. In previous research, we established and characterized two novel sinonasal NUT carcinoma cell lines from a surgical specimen. To gain a deeper understanding of the disease, we conducted a multiplex immunofluorescence study on the surgical specimen from which these cell lines were derived. Materials and Methods: A formalin-fixed, paraffin-embedded surgical specimen from a 28-year-old man who was diagnosed with T4bN0M0 sinonasal NUT carcinoma was used in this study. The patient underwent two cycles of induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil at another institution, followed by surgical resection at the University of Texas MD Anderson Cancer Center. Opal 7-color multiplex immunofluorescence was performed on the surgical specimen, using antibodies for pan-cytokeratin (CK, clone 80), CD3, CD8, PD-L1, CD68, CD56/NCAM (an NK cell marker), and DAPI. Tissue identification, marker detection, and data extraction were conducted using QuPath (version 0.5.1). Tumor cells with low CK expression were categorized as 'CK low ' cells, and their proportion within the tumor was calculated as CK low / (CK low + CK + ) x 100. Results: Fifty-four percent of the tumor cells were classified as CK low , indicating heterogeneity within this tumor sample. CD8 + tumor-infiltrating lymphocytes were present at only 0.14%, suggesting that this specimen exhibits a less immunogenic 'cold' tumor profile. The percentage of PD-L1-positive tumor cells, which is associated with a better response to immunotherapy in various tumor types, was less than 0.2%. Furthermore, the percentage of CD68 + PD-L1 + macrophages, another indicator for response to certain types of immunotherapies, was found to be less than 5%. Conclusion: The sample of sinonasal NUT carcinoma that we analyzed exhibited heterogeneous cytokeratin expression and low immunogenic characteristics. Given that NUT carcinoma is primarily driven by a single fusion oncoprotein, it has a low tumor mutational burden, which may align with these findings. Since conventional treatments for NUT carcinoma, such as chemotherapy and radiation therapy, have shown very limited success, it is essential to develop strategies to address the tumor immune microenvironment and to incorporate immunotherapy and potential new targetable therapies effectively. We plan to create an advanced panel with additional markers and include more tumor samples to further investigate the biology of sinonasal NUT carcinoma in our future studies. Publication History Article published online: 27 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2026-01-28 | NUTM1-rearranged sarcoma arising in the descending colon presenting as a submucosal mass: a case report
Abstract Purpose NUT midline carcinoma family number 1 ( NUTM1) -rearranged sarcoma is extremely rare and characterized by NUTM1 gene rearrangement with variable morphological features. The gastrointestinal tract is one of the most common sites. These sarcomas showing similar histopathological findings have yielded poor clinical outcomes. Case presentation A healthy 52-year-old Japanese man presented with a solitary, localized submucosal mass, 3 cm in size, in the descending colon. Microscopically, the sarcoma comprised sheet-like proliferation of plump epithelioid/rhabdoid cells, fibrosarcoma-like spindle cells showing an intersecting fascicular pattern, and neoplastic cell nests in hyalinized stroma. Immunohistochemistry (IHC) revealed that sarcoma cells were diffusely positive for NUT. Fluorescence in situ hybridization (FISH) confirmed NUTM1 gene rearrangement. Recurrences in the retroperitoneum at 9 and 21 months after initial surgery were surgically excised. The histopathological features and the results of IHC and FISH for the sarcoma coincided with those of previously reported NUTM1 -rearranged sarcoma occurring in the colon. The sarcoma recurred three times within a short time after the initial surgery. Therefore, the behavioral aggressiveness and site in which the sarcoma arose were also consistent with those of NUTM1 -rearranged sarcoma in the colon. Of note, these recurrent sarcomas comprised only a plump epithelioid/rhabdoid cell component. Conclusion We reported here an unusual sarcoma with unexpected poor outcomes. Our case may provide additional useful information regarding this extremely rare sarcoma of colonic submucosal origin.
2026-01-28 | NUT carcinoma of the cheek managed with chemotherapy and surgical resection.
NUT(Nuclear Protein in Testes) carcinoma is a rare and aggressive malignancy characterised by rearrangements of the NUTM1 gene, primarily affecting midline structures in children and adults. We report a middle childhood male who presented with a left cheek swelling initially noticed 2 months earlier, surgically resected 1 month ago and recurred over the past week. Histopathology revealed a poorly differentiated neoplasm, with immunohistochemistry showing diffuse CK5/6, P63, P40 expression, intact SMARCA4, P16 negativity and speckled NUT nuclear staining confirming NUT carcinoma. Imaging demonstrated local extension with small-volume nodal metastases. He was treated with nine cycles of VDC-IE(vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide) chemotherapy given at 3-week intervals, complicated by transient iron deficiency anaemia, followed by surgical excision with neck dissection and fibular flap reconstruction. Post-treatment positron emission tomography scan showed no metabolically active disease. Maintenance therapy with the histone deacetylase inhibitor vorinostat was initiated. This case highlights the importance of early recognition, multimodal therapy and emerging targeted treatment in improving outcomes for NUT carcinoma.
Access all drug discovery papers and probability of success in trials forecasts:
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Drug Discovery Landscape
4 orphan drug designations for NUT midline carcinoma.
4 orphan drug designations for NUT midline carcinoma.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
small molecule (heterocyclic compound) that epigenetically regulates gene expression through bromodomain and extra-terminal domain inhibition | small molecules | FDA | 2025-10-24 | — | Zenith Epigenetics Ltd. |
(R)-N-(2-fluorobenzyl)-2,4-dimethyl-1-(oxetan-3-ylmethyl)-3-oxo- 1,2,3,4-tetrahydroquinoxaline-6-carboxamide | small molecules | FDA | 2025-07-09 | — | Deepcure Inc. |
mesylate synthetic small molecule inhibitor of HDAC and PI3K | small molecules | FDA | 2016-09-06 | — | Curis, Inc. |
2-[(4S)-6-(4-chlorophenyl)-1,7,8-trimethylthiophenol[3,2-f]1,2,4-triazolo[4,3-a]1,4-diazepin-4-yl]-N-[3-(4-methylpiperazinyl)propyl]acetamide | small molecules | FDA | 2015-09-29 | — | Genentech, Inc (a Roche Group Member) |
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