NHWD-870

Nuclear protein in testis (NUT) carcinoma (NC) is a rare, highly aggressive neoplasm, usually accompanying with NUTM1 (NUT midline carcinoma family member 1) gene fusions. Primary thyroid NC is clinically rare and to date there is no established treatment guideline available for NC. We report a case of histopathologically confirmed thyroid NC and provide reference for diagnosis and treatment.

We presented a 32-year-old female admitted to hospital with "painful neck swelling and progressive dysphagia". Preoperative ultrasound-guided core needle aspiration biopsy suggested a poorly differentiated tumor. Considering the tumor was totally unresected on computed tomography (CT) scan, a partial thyroidectomy was performed to obtain sufficient tissue for a clear diagnosis. Histopathological specimens showed features of sudden keratosis. Strong immunoreactivity with NUT was detected by immunohistochemistry (IHC) and thus confirmed the diagnosis of NC. CK5/6, P40 and P63 were partially positive exclusively in keratosis area. Next-generation sequencing (NGS) and RNA sequencing results revealed a NSD3-NUTM1 fusion. The patient was treated with a combined regimen of radiotherapy of 70 Gy, chemotherapy with paclitaxel (albumin-bound), immunotherapy with nivolumab, targeted therapy with anlotinib and BET inhibitor NHWD-870, but the patient died 7 months after diagnosis.

Thyroid NC is a rare and distinct pathological subset of NUT carcinoma with a higher rate of NSD3-NUTM1 fusion. In the clinical diagnosis process, we recommended performing NUT IHC for poorly differentiated thyroid tumors. Gene rearrangement detection is also helpful for diagnosis and treatment. At present, surgery and radiation are still first choices for NC, and advances in targeted immunotherapy such as bromodomain and end motif inhibitors (BETi) may bring better treatment options to patients.

Psoriasis is a chronic, recurrent, inflammatory dermatosis accompanied by excessive activation of dendritic cells (DCs), which are primarily responsible for initiating an immune response. The bromodomain and extraterminal domain (BET) family plays a pivotal role in the transcriptional regulation of inflammation and its inhibitors can downregulate DCs maturation and activation. Here we investigated the effect of NHWD-870, a potent BET inhibitor, on inflammation in an imiquimod (IMQ)-induced psoriasis-like mouse model and murine bone marrow-derived dendritic cells (BMDCs) stimulated by lipopolysaccharide (LPS) and IMQ. Application of NHWD-870 significantly ameliorated IMQ-triggered skin inflammation in mice, and markers associated with DC maturation (CD40, CD80 and CD86) were decreased in skin lesions, spleen and lymph nodes. Additionally, NHWD-870 reduced LPS or IMQ induced DCs maturation and activation in vitro, with lower expression of inflammatory cytokines [interleukin (IL)-12, IL-23, tumor necrosis factor-α, IL-6, IL-1β, chemokine (C-X-C motif) ligand (CXCL)9 and CXCL10]. In addition, we found that interferon regulatory factor 7 (IRF7) significantly increased during DCs maturation, and inhibition of IRF7 could impair BMDCs maturation and activation. What's more, IRF7 was highly expressed in both psoriatic patients and IMQ-induced psoriasis-like mice. Single-cell RNA sequencing of normal and psoriatic skin demonstrated that IRF7 expression was increased in DCs of psoriatic skin. While NHWD-870 could inhibit IRF7 and phosphorylated-IRF7 expression in vivo and in vitro. These results indicate that NHWD-870 suppresses the maturation and activation of DCs by decreasing IRF7 proteins which finally alleviates psoriasis-like skin lesions, and NHWD-870 may be a potent therapeutic drug for psoriasis.