Multimodal therapy approaches for NUT carcinoma (NC)

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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.