# Overcoming Limitations of BETInhibition in NUT Carcinoma

> **NIH NIH U01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $558,775

## Abstract

Project Summary/Abstract. NUT-fusion oncoproteins, most commonly BRD4-NUT, drive NUT carcinoma
(NC), an aggressive, poorly differentiated squamous cancer with a 6.5-month median survival and < 20% 3-
year survival. NC predominantly affects adolescents and young adults and, with no routinely effective therapy,
has a critical unmet need. BRD4-NUT drives growth by altering histone modifications and chromatin 3D
structure to upregulate expression of pro-growth genes. We demonstrated that BET bromodomain inhibitors
reverse these epigenetic modifications and block tumor growth. These findings led to the treatment of NC and
numerous other malignancies with BET inhibitors. However, the clinical efficacy of BET inhibitor monotherapy
is limited, indicating that BET inhibitors alone do not fully address NC biology. The goal of this proposal is to
overcome the limitations of BET inhibition in NC and therefore improve patient outcomes by identifying
targetable mechanisms of gene regulation that maintain NC growth.
Using our combined expertise in translational NC cancer biology (CA French) and chromatin biology (KP Eagen)
we will take a two-pronged approach to improve NC treatment through mechanism-based target discovery. Both
prongs share the premise that identifying factors that cooperate with BRD4-NUT to promote NC growth will
lead to new therapeutic targets. Our first Aim is based upon our recent discovery that repression of tumor
suppressor genes by the histone methyltransferase EZH2 complements oncogene activation by BRD4-NUT.
Simultaneous inhibition of EZH2 and BRD4-NUT synergistically blocks NC growth in vitro and in vivo. However,
the precise mechanism of synergy remains unknown. Additionally, toxicity was observed in some xenograft
models, and thus toxicity in humans is likely. Therefore, we propose to identify more precise therapeutic targets
by determining key factors that mediate the oncogenic synergy between EZH2 and BRD4-NUT. Our second Aim
is motivated by the discovery of a novel MLL1::NUTM1 fusion in a patient. Our proteomics data indicate that
MLL1 and its key binding partner MENIN are both present in the BRD4-NUT oncogenic complex providing
biochemical evidence that this fusion may reveal new factors that cooperate with BRD4-NUT. Accordingly,
inhibiting the interaction between MLL1 and MENIN induces differentiation and blocks growth of NC cells. The
combination of MENIN-MLL1 with EZH2 inhibition synergistically blocks NC growth in vitro. This data suggests
that combination therapy with MENIN-MLL1 and EZH2 inhibitors could potentially replace BET inhibition, which
we will test in pre-clinical models of NC.
Aim 1. Determine the mechanism by which EZH2 cooperates with BRD4-NUT to drive NC growth.
Aim 2. Elucidate the role of MENIN in BRD4-NUT oncogenic function.

## Key facts

- **NIH application ID:** 10984705
- **Project number:** 1U01CA294062-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Kyle Patrick Eagen
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $558,775
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10984705

## Citation

> US National Institutes of Health, RePORTER application 10984705, Overcoming Limitations of BETInhibition in NUT Carcinoma (1U01CA294062-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10984705. Licensed CC0.

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