Multimodal Therapy Approaches for NUT Carcinoma by Dual Combination of Oncolytic Virus Talimogene Laherparepvec with Small Molecule Inhibitors

Sep 21, 2026

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NUT (nuclear-protein-in-testis) carcinoma (NC) is a highly aggressive tumor with limited effectiveness of current regimens, which offer a median survival of only six months. Prior findings suggest the oncolytic herpes simplex virus T-VEC is functional in NC. To identify additional partners, T-VEC and five small molecule inhibitors were tested alone and in combination in human NC cell lines, showing dual combinations produced greater tumor cell reduction than monotherapies. The T-VEC plus small molecule inhibitor regimen reduced c-Myc expression more strongly and earlier than T-VEC alone, supporting multimodal combinatorial therapy for this resistant cancer.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages18

Reading Time45 min

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Abstract

Introduction

NUT carcinoma background and molecular features

Current treatment limitations

Rationale for multimodal oncolytic virotherapy

viruses Article Multimodal Therapy Approaches for NUT Carcinoma by Dual Combination of Oncolytic Virus Talimogene Laherparepvec with Small Molecule Inhibitors Stavros Sotiriadis 1, Julia Beil 1,2, Susanne Berchtold 1, Irina Smirnow 1, Andrea Schenk 1 and Ulrich M. Lauer 1,2, * Citation: Sotiriadis, S.; Beil, J.; Berchtold, S.; Smirnow, I.; Schenk, A.; Lauer, U.M. Multimodal Therapy Approaches for NUT Carcinoma by Dual Combination of Oncolytic Virus Talimogene Laherparepvec with Small Molecule Inhibitors. Viruses 2024, 16, 775. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)v16050775 Academic Editor: Craig Meyers Received: 4 April 2024 Revised: 23 April 2024 Accepted: 9 May 2024 Published: 14 May 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Department of Medical Oncology and Pneumology, Virotherapy Center Tübingen (VCT), Medical University Hospital, 72076 Tübingen, Germany; [stavros.sotiriadis@med.uni-tuebingen.de](stavros.sotiriadis@med.uni-tuebingen.de) (S.S.) 2 German Cancer Consortium (DKTK), Partner Site Tübingen, a Partnership between DKFZ and University Hospital Tübingen, 72076 Tübingen, Germany * Correspondence: ulrich.lauer@uni-tuebingen.de; Tel.: +49-(0)7071-29-83190 Abstract: NUT (nuclear-protein-in-testis) carcinoma (NC) is a highly aggressive tumor disease. Given that current treatment regimens offer a median survival of six months only, it is likely that this type of tumor requires an extended multimodal treatment approach to improve prognosis. In an earlier case report, we could show that an oncolytic herpes simplex virus (T-VEC) is functional in NC patients. To identify further combination partners for T-VEC, we have investigated the anti-tumoral effects of T-VEC and five different small molecule inhibitors (SMIs) alone and in combination in human NC cell lines. Dual combinations were found to result in higher rates of tumor cell reductions when compared to the respective monotherapy as demonstrated by viability assays and real-time tumor cell growth monitoring. Interestingly, we found that the combination of T-VEC with SMIs resulted in both stronger and earlier reductions in the expression of c-Myc, a main driver of NC cell proliferation, when compared to T-VEC monotherapy. These results indicate the great potential of combinatorial therapies using oncolytic viruses and SMIs to control the highly aggressive behavior of NC cancersand probably will pave the way for innovative multimodal clinical studies in the near future. Keywords: NUT carcinoma; talimogene laherparepvec; T-VEC; virotherapy; small molecule inhibitors; combination therapy; Myc 1. Introduction NUT carcinoma (NC), formerly known as NUT midline carcinoma (NMC), is avery rare cancer type causing very aggressive and highly resistant tumors that can arise anywhere in the body, but often appear along midline structures (head, neck, mediastinum) [1,2] . NC is well characterized by one single genetic translocation involving the NUT midline carcinoma family member 1 (NUTM1) gene, formerly known as the nuclear-protein-in-testis (NUT) gene, on chromosome 15q13 [3,4] . NUTM1 can undergo fusion with several partners, such in most cases with BRD4 (on chromosome 19q13) [5,6], but also, e.g., BRD3 (on chromosome 9q34) [7] or NSD3 (on chromosome 8p11-12) [8] . Although the exact function of NUTM1 is not yet completely known, it is associated with poorly differentiated epithelial carcinomas that commonly occur in young adults and show an aggressive growth dynamic especially when these cells carry the BRD4-NUTM1 fusion gene [3,7] . BRD4 belongs to the bromodomain and extra-termina

FAQs

What is the clinical challenge in treating NUT carcinoma (NC)?

NC is highly aggressive and resistant, and current treatment regimens yield a median survival of about six months. The disease is also underdiagnosed because it can be misidentified as other tumor types, leading to untargeted therapies.

How were T-VEC and small molecule inhibitors evaluated in this study?

The study tested T-VEC and five small molecule inhibitors both as single agents and as combinations in human NC cell lines.

What did the dual combination of T-VEC and small molecule inhibitors improve?

Dual combinations produced higher tumor cell reduction rates than the corresponding monotherapies, and the T-VEC plus small molecule inhibitor combination drove stronger and earlier reductions in c-Myc expression compared with T-VEC alone.

Sep 21, 2026

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