# Role of NSD3 in regulation of cancer pathogenesis

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $612,325

## Abstract

ABSTRACT
 Our overarching goal is to elucidate the mode of action of and evaluate the therapeutic potential of the
epigenetic regulatory factor NSD3 in the regulation of lung squamous cell carcinoma (LUSC) pathogenesis. Lung
cancer is the most common cause of cancer-related mortality in the United States and worldwide, leading to over
a 1.8 million deaths each year. LUSC is the second most common subtype of lung cancer, accounting for ~30%
of all cases and tragically over 40,000 deaths each year in the US alone. While new targeted therapies have
shown promise in other malignancies, unfortunately, to date, there are no approved targeted therapies for LUSC.
Thus, there is a major unmet need to uncover new, clinically actionable, and compelling targets for the
development of new medicines to ultimately treat this difficult disease. A central hypothesis to be tested here is
that the histone H3 lysine 36 (H3K36) di-methyltransferase enzyme NSD3 is a promising epigenetic target for
the treatment of LUSC. In preliminary work we found that NSD3, which is commonly amplified in LUSC, is a
major driver of LUSC pathogenesis in mouse and human models of this cancer. In our proposal, we will
investigate the role of the NSD3-H3K36me2 axis in lung cancer in vivo and explore the molecular and epigenetic
basis of NSD3-driven tumorigenesis.
 In Aim 1 we investigate the role of NSD3 in LUSC pathogenesis. We have developed novel mouse models
that recapitulate the most common genetic alterations in human LUSC, including NSD3 amplification, and
incorporated an inducible dual-recombinase approach to allow study of multi-step tumorigenesis in vivo. This
system will be used to dissect the specific functions for NSD3 in LUSC tumor initiation, progression,
maintenance, and metastatic transition using conditional NSD3 gain-of-function and knockout mice. A multistep
approach will also enable genetic validation of NSD3 as potential therapeutic target in advanced LUSC, a stage
for which new therapies are urgently needed. In Aim 2 we will elucidate the epigenetic pathways reguated by
the NSD3-H3K36me2 axis, utilizing new cutting-edge epigenomic technologies. We will also explore the role of
NSD3 in promoting intratumoral heterogeneity in human and mouse models of LUSC at the single cell level.
Together, this work will be the first to evaluate the therapeutic potential and mechanism-of-action of NSD3 in
LUSC.

## Key facts

- **NIH application ID:** 10817063
- **Project number:** 5R01CA278940-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Or P. Gozani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $612,325
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10817063

## Citation

> US National Institutes of Health, RePORTER application 10817063, Role of NSD3 in regulation of cancer pathogenesis (5R01CA278940-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10817063. Licensed CC0.

---

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