Genomic profiling of solid tumors harboring BRD4-NUT and response to immune checkpoint inhibitors

Riess, Jonathan W.; Rahman, Shaila; Kian, Waleed; Edgerly, Claire; Heilmann, Andreas; Madison, Russell; Ramkissoon, Shakti; Klaitman, Shai Shlomi; Chung, Jon; Trabucco, Sally E.; Jin, Dexter X.; Alexander, Brian M.; Klempner, Samuel J.; Albacker, Lee A.; Frampton, Garrett M.; Roisman, Laila C.; Miller, Vincent A.; Ross, Jeffrey S.; Schrock, Alexa B.; Gregg, Jeffrey P.; Peled, Nir; Sokol, Ethan S.; Ali, Siraj M.

doi:10.1016/j.tranon.2021.101184

Cited by 13 publications

(6 citation statements)

References 28 publications

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“…This study evaluated 55 patients (36 men and 19 women) among the 35 articles [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ] with a mean age of 41.4 years (range, 6–82). The male to female ratio was approximately 1.89 to 1.…”

Section: Resultsmentioning

confidence: 99%

Diagnosis, Treatment and Prognosis of Primary Pulmonary NUT Carcinoma: A Literature Review

Yuan

Guo

2022

Current Oncology

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NUT carcinoma is a rare, highly lethal cancer characterized with the rearrangement of the nuclear protein in testis (NUT) gene on chromosome 15q14, which primarily occurs in the midline organs. Primary pulmonary NUT carcinoma (NC) lacks characteristic clinical manifestations, which leads to the high rate of misdiagnose and nonstandard treatment. To date, fewer than one hundred cases have been reported worldwide. Here, a comprehensive literature search involving a total of 35 articles with 55 patients was conducted in this paper. We reviewed and analyzed the associated clinical and pathological characteristics, the efficacy of various treatment options and the prognosis. Pulmonary NC mainly occurred in middle young-aged men (median age, 36) with no smoking history (2:1) and would present with symptoms of cough (63.6%), dyspnea (29.5%), chest pain (18.2%) and hemoptysis (18.2%). The initial imaging frequently revealed large and irregular lesions in the lower lobe (46.5%) of the left or right lungs; lymph node metastasis was also prevalent (91.9%). A focal squamous differentiation with abrupt keratinization often occurred in the undifferentiated or poorly differentiated (93.75%) tumor cells, with abundant necrosis and numerous neutrophils infiltrated. The mean overall survival (OS) in patients of this malignant disease was 6.21 months, and the median OS was 4.4 months. According to our results, this disease is sensitive to radiotherapy, and chemoradiotherapy (either concurrent chemoradiotherapy or sequential chemoradiotherapy) was the most efficient therapeutic regimen to prolong the OS of patients with pulmonary NC.

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Section: Resultsmentioning

confidence: 99%

Diagnosis, Treatment and Prognosis of Primary Pulmonary NUT Carcinoma: A Literature Review

Yuan

Guo

2022

Current Oncology

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“…Their data demonstrate that TMB ranges from intermediate (between 5 and 20 mut/mb) in an adult case to low (<5 mut/mb) in pediatric cases. Other studies have reported low TMB and stable microsatellites in NC (55). Riess et al described 31 solid tumor cases harboring a BRD4::NUT translocation.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathological molecular characterizations of sinonasal NUT carcinoma: a report of two cases and a literature review

Chen,

Li,

Jiang

2024

Front. Oncol.

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BackgroundNuclear protein in testis (NUT) carcinoma (NC) is a rare, aggressive tumor with a typical NUTM1 gene rearrangement.MethodsHerein, we report a series of 2 cases of sinonasal NC: one in a 16-year-old woman and one in a 37-year-old man. Immunohistochemistry (IHC) staining for NUT (C52B1), fluorescence in situ hybridization (FISH), and next generation sequencing (NGS) sequencing were performed to investigate the morphological and genetic features of sinonasal NC.ResultsThe two cases presented similar pathological features and IHC markers, and typical morphological changes, including undifferentiated cells and abrupt keratinization, were observed, with numerous mitotic figures and widespread tumor necrosis. Diffuse expression of NUT, CK, p63, and p40 was noted, while the tumors were negative for synaptophysin, chromogranin A, S-100, EBV-ISH, and PD-L1. Both tumors harbored a NUTM1 rearrangement. Subsequent sequencing revealed a rare BRD3::NUTM1 fusion and a classic BRD4::NUTM1 fusion. In addition, MCL1 copy number gain (2.1), low tumor mutation burden and stable microsatellites, were also confirmed. Case 1 received surgery and chemoradiotherapy but died 13 months after local recurrence and subsequent lung and bone metastasis. Case 2 underwent chemoradiotherapy and unfortunately died from the disease 6 months later. A review of all previously reported cases of sinonasal NCs (n=55) revealed that these tumors occur more frequently in female pediatric patients (n=11, male: female =3:8), whereas this sex difference is not observed in adult patients (n=44, male: female =23:21). The median survival times of pediatric and adult patients were 17 and 13.8 months, respectively.ConclusionSinonasal NC presents typical undifferentiated or poorly differentiated cells, abrupt keratinization features and heterogeneous genotypes, including BRD4::NUTM1 and BRD3::NUTM1 fusions, with low tumor mutation burden and stable microsatellites.

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“…However, a subsequent phase III trial failed to demonstrate an additive effect of combining the two treatments in the first-line setting (NCT02263508) [ 43 ] but studies evaluating the combination in the neoadjuvant and post-PD-(L)1 setting (NCT04068181), and also in tumor types other than melanoma (NCT02509507), are still ongoing. Given that the PD-1/PD-L1 blockade has now also been successfully tested in NC patients [ 44 ], a triple combinatorial approach consisting of T-VEC, iBET compounds, and immune checkpoint inhibitors may further improve therapeutic efficacy. With T-VEC already clinically approved and both iBET compounds already under clinical investigation, the dual approach, as well as a possible triple approach with anti-PD-1/anti-PD-L1, offers the potential for rapid development from “bench to bedside”.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Oncolytic Herpes Simplex Virus T-VEC Combined with BET Inhibitors as an Innovative Therapy Approach for NUT Carcinoma

Ohnesorge

Berchtold

Beil

et al. 2022

Cancers

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NUT carcinoma (NC) is an extremely aggressive tumor and current treatment regimens offer patients a median survival of six months only. This article reports on the first in vitro studies using immunovirotherapy as a promising therapy option for NC and its feasible combination with BET inhibitors (iBET). Using NC cell lines harboring the BRD4-NUT fusion protein, the cytotoxicity of oncolytic virus talimogene laherparepvec (T-VEC) and the iBET compounds BI894999 and GSK525762 were assessed in vitro in monotherapeutic and combinatorial approaches. Viral replication, marker gene expression, cell proliferation, and IFN-β dependence of T-VEC efficiency were monitored. T-VEC efficiently infected and replicated in NC cell lines and showed strong cytotoxic effects. This implication could be enhanced by iBET treatment following viral infection. Viral replication was not impaired by iBET treatment. In addition, it was shown that pretreatment of NC cells with IFN-β does impede the replication as well as the cytotoxicity of T-VEC. T-VEC was found to show great potential for patients suffering from NC. Of note, when applied in combination with iBETs, a reinforcing influence was observed, leading to an even stronger anti-tumor effect. These findings suggest combining virotherapy with diverse molecular therapeutics for the treatment of NC.

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Genomic profiling of solid tumors harboring BRD4-NUT and response to immune checkpoint inhibitors

Cited by 13 publications

References 28 publications

Diagnosis, Treatment and Prognosis of Primary Pulmonary NUT Carcinoma: A Literature Review

Diagnosis, Treatment and Prognosis of Primary Pulmonary NUT Carcinoma: A Literature Review

Clinicopathological molecular characterizations of sinonasal NUT carcinoma: a report of two cases and a literature review

Efficacy of Oncolytic Herpes Simplex Virus T-VEC Combined with BET Inhibitors as an Innovative Therapy Approach for NUT Carcinoma

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