# Developing a clinically-relevant genetically engineered mouse model for Nut carcinoma

> **NIH NIH R37** · MICHIGAN STATE UNIVERSITY · 2024 · $418,571

## Abstract

Title: Developing a Clinically-Relevant Genetically Engineered Mouse Model of NUT Carcinoma
Project Summary:
A testis-specific gene called Nuclear protein in testis (NUTM1) has emerged as a recurrent fusion partner of
oncogenic fusion genes in poorly understood neoplasms. Among these neoplasms, NUT carcinoma (NC) is the
most aggressive and is the paradigm for the study of NUTM1 fusion gene-associated cancers. The majority of
NCs are associated with a chromosome translocation that joins together gene fragments of the Bromodomain-
containing protein 4 (BRD4) and the NUTM1 protein. Clinical research and experimental research based on in
vitro cell culture systems has established the BRD4-NUTM1 fusion protein as the sole driver of NC. This project
will address two vital current issues in NC research:
Issue 1: Paradoxically, although BRD4-NUTM1 suffices to drive NC, ectopic expression of BRD4-NUTM1 in
non-NC cells is unequivocally cytotoxic. Whether there is a specific cell type in which NCs originate — and how
these cells are able to circumvent the cytotoxic effects of BRD4-NUTM1 — is a mystery.
Issue 2: As the driver of NC oncogenesis, BRD4–NUTM1 is the most promising drug target for treating NC.
However, targeted therapy strategies directed against the BRD4 fragment of BRD4-NUTM1 have been
disappointing, largely because of intolerable side effects that are due to endogenous BRD4 being broadly
expressed. Targeting the testis-specific NUTM1 protein has the potential to circumvent most systematic side
effects in male patients and all side effects in female patients, yet this strategy has not been explored in a
physiological context.
Building on our expertise in genome editing technology and unique resources in genetically engineered mouse
lines, we will address these two vital NC issues by building the first genetically engineered mouse model that
can recapitulate the tissue and physiological context of NC. Aim 1 will build and characterize an inducible
chromosome translocation mouse model for NC. Our model mice will express reporter genes for tracing and
isolating NC cells that express BRD4-NUTM1. Aim 2 will identify the NC cell type of origin by analyzing genomic
data from NC-originating normal cell populations and cells in early stages of NC development. Aim 3 will leverage
in vivo inducible BRD4-NUTM1 protein degradation to model NUTM1 targeting in order to establish a targeting
strategy for treating NC with minimal side effects.
Overall Impact. This project will produce a genetically engineered mouse model of Nut Carcinoma as an entirely
new experimental tool for studying oncogenic mechanisms of BRD4-NUTM1. Our studies will transform
understanding of early-stage NC and spur therapeutic development to treat NC without intolerable side effects.
This project will also shed light on mechanisms and treatment strategies for other poorly understood cancers
with NUTM1 fusion genes.

## Key facts

- **NIH application ID:** 10760244
- **Project number:** 5R37CA269076-02
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Bin Gu
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $418,571
- **Award type:** 5
- **Project period:** 2023-01-05 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10760244

## Citation

> US National Institutes of Health, RePORTER application 10760244, Developing a clinically-relevant genetically engineered mouse model for Nut carcinoma (5R37CA269076-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10760244. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*