Multimodal therapy approaches for NUT carcinoma (NC)

NUT癌（NC）是一种罕见且非常具有侵袭性的癌症，通常对治疗有抵抗力。诊断后的中位生存时间为6至9个月。迄今为止，仍然没有有效的治疗NC的方法。同样，目前没有指南，目前的治疗方法是基于几个肿瘤学家之间的讨论，他们每个人都有治疗这种疾病的病例经验。人们强烈认为，这种类型的癌症不能通过单一的治疗方式来控制，而只有以不同方式发挥其功效的新型药物的组合才能阻止这种侵袭性疾病。在这种情况下，溶瘤病毒疗法（OV）代表了一种新的治疗方法，在我们的工作之前尚未测试用于治疗NC。然而，似乎需要与抗增殖化合物的组合来弥合差距，直到免疫病毒疗法变得有效，所述抗增殖化合物能够至少在最初停止这种侵袭性肿瘤类型的快速生长。第一份手稿报告了用溶瘤单纯疱疹病毒T-VEC联合两种iBET BI 894999和GSK 525762治疗的BRD 4-NUTM 1细胞系中获得的有希望的数据，现已被Cancers杂志接受发表。因此，我们的第一个目的是表征含有NUTM 1而不是BRD 4的融合伴侣（包括BRD 3和NSD 3）的NC肿瘤细胞系，关于它们对溶瘤病毒的敏感性，作为（i）单一疗法和（ii）双重疗法（OV与iBET化合物组合）。此外，NC对OV的应答模式将通过聚焦于例如干扰素（IFN）信号传导途径（包括STING和其他推定的靶基因）中的差异来阐明。该项目最重要的部分可能是开发一种有效的三联疗法，包括OV + iBET作为标准疗法，然后通过分配到其他有前途的NC基础分子疗法组（包括HDACi，p300/CBPi，CDK 4/6 i）的候选药物进一步增强。最后，将从患者材料开发新的NC肿瘤细胞系和模型系统，如NC肿瘤类器官，作为NC体内实验的中间步骤，我们迄今为止在NC细胞系的组合治疗中获得的知识将被转移和应用。

NUT carcinoma (NC) is a rare and very aggressive form of cancer that is very often resistant to treatment. The median survival time after diagnosis ranges from 6 to 9 months. To date, there is still no effective treatment for NC. Likewise, there are no guidelines and current treatment approaches are based on discussions among a few oncologists who each have case experiences in treating this disease. It strongly is believed that this type of cancer cannot be controlled by a single therapeutic modality, but that only a combination of novel agents that exert their efficacy in different ways can stop this aggressive disease. In this context, oncolytic virotherapy (OV) represents a novel therapeutic approach that prior to our work has not been tested for the treatment of NC. However, combinations with antiproliferative compounds, which are able to halt at least initially the rapid growth of this aggressive tumor type, seem to be needed to bridge the gap until immunovirotherapy becomes effective. A first manuscript reporting promising data obtained in BRD4-NUTM1 cell lines treated with the oncolytic herpes simplex virus T-VEC in combination with the two iBETs BI894999 and GSK525762 has now been accepted for publication by the journal Cancers. Thus, our first objective is to characterize NC tumor cell lines that harbor fusion partners for NUTM1 other than BRD4, including BRD3 and NSD3, with respect to their sensitivity to oncolytic viruses as (i) monotherapy and (ii) dual therapy (OV in combination with iBET compounds). Furthermore, NC response patterns to OVs will be elucidated by focusing e.g. on differences in the interferon (IFN) signaling pathway (including STING and other putative target genes). Probably the most important part of this project is to develop an effective triple therapy approach, consisting of OVs + iBETs as standard therapy, which will then be further enhanced by candidates assigned to the group of other promising NC basic molecular therapeutics (including HDACi, p300/CBPi, CDK4/6i). Finally, new NC tumor cell lines and model systems, such as NC tumor organoids, will be developed from patient material, to which, as an intermediate step to NC in vivo experiments, our knowledge gained so far in the combinatorial treatment of NC cell lines will be transferred and applied.