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Neumann et al. J Transl Genet Genom 2022;6:353-60 https://dx.doi.org/10.20517/jtgg.2022.06 Page 357

When adding the search term “treatment,” 109 articles were found. No standard treatments have been
established for NC; however, a multi-modality approach with surgery, systemic chemotherapy, and
radiation therapy remains the backbone of current standard of care. Given the rarity of this disease, it is
difficult to evaluate the efficacy of various treatment combinations. In a report utilizing the International
NUT Midline Carcinoma Registry, 40 patients with head and neck involvement were analyzed; the biggest
predictors for improved OS was initial surgery, with or without chemoradiation (chemoRT) or radiation
(P = 0.04; median PFS was 6.6 months, and mOS 9.7 months) and complete resection with negative margins
(P = 0.01). There were only three long-term survivors at 35, 72, and 78 months, with overall 2-year survival
of 30%; all three cases underwent surgery followed by adjuvant chemoRT or radiation alone . When
[18]
postoperative chemoRT is offered, cisplatin, taxanes, and alkylating agents are the most commonly used
agents, albeit with limited success.

More recently, bromodomain inhibitors (BETis) and histone deacetylase inhibitors (HDACis) have
emerged as promising agents in combination with chemotherapy, and there have been some benefits seen
with immune checkpoint inhibitors and CDK9 inhibitors [19-21] . Epigenetics in cancer has shown that human
cancer cells exploit both genetic and epigenetic abnormalities. HDACi has been proposed for the
BRD4-NUT fusion protein since the gene activates histone acetyl-transferase p300, which can be reversed
by hyperacetylating histones artificially with HDACi, increasing transcription of pro-differentiative
disease . These epigenetic changes are potentially reversible with agents such as HDACis and histone
[22]
methyltransferase inhibitors (HMTis).

When adding “BET” to the search term, 19 articles were found, the first one dating to 2012. It is
hypothesized that BRD-NUT fusion proteins function as oncogenes by sequestering histone
[23]
acetyltransferase activity, thus blocking differentiation . BETis bind the acetyl-lysing pocket of
bromodomains BD1 and BD2, thus being of possible use in treating tumors driven by BET fusion proteins
(including BRDT, BRD2, BRD3, and BRD4) by blocking the binding of BRD-NUT proteins to chromatin
and thus resulting in terminal differentiation of NC cells . BETis are being extensively studied in both solid
[24]
and liquid tumors. The acetyl-histone binding of BRD4-NUT bromodomains is required for the expression
[25]
of MYC, and bromodomains are required to enrich the MYC promoter . A phase I and II, open-label,
dose-escalation study with the BETi molibresib was conducted and enrolled 65 total patients with various
tumor types, including 19 patients with NC. The most frequent treatment-related adverse effects were
thrombocytopenia (51%), gastrointestinal events including nausea, vomiting, diarrhea, dysgeusia
(22%-42%), anemia (22%), and fatigue (20%). Among the 19 patients with NC, four had partial response, 8
stable disease and 4 were progression-free for more than 6 months .
[26]
[27]
Birabresib was recently examined in a Phase 1b trial with 46 patients, 10 of whom had NC . Six patients
had partial response or stable disease. Stathis et al. described the use of Birabresib in four NC patients,
describing dramatic and rapid response in two patients (OS of 18 and 19 months) and stable disease in a
[28]
third patient . All patients died of the disease but the mOS was longer than reported in the largest
retrospective study, with OS of 6.7 months reported by Bauer et al. and 9.7 months reported by Chau and
colleagues [7,18] . Adverse effects were found to limit the use of BETi, with the most common toxicities being
diarrhea, nausea, decreased appetite, and thrombocytopenia. Given resistance to restoration of MYC
[29]
expression, Liao et al. proposed combining BETi with cyclin-dependent kinase (CDK)4/6 inhibitors .
Clinical trials are currently being performed with CUDC-907, a combined histone deacetylase inhibitor
(HDACi)/phosphatidylinositol 3-kinase inhibitor (PI3K inhibitor) for NC [NCT02307240].