# Desmoplastic small round cell tumor: harnessing new insights and new models

> **NIH NIH U01** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $527,904

## Abstract

The desmoplastic small round cell tumor (DSRCT) remains one of the most lethal adolescent/young adult
(AYA) sarcomas. The EWSR1-WT1 gene fusion is the primary and defining genetic driver alteration in this
sarcoma but a better understanding of EWSR1-WT1 oncogenic mechanisms is needed to identify novel,
rational therapeutic strategies that will be more effective. We propose to address these knowledge gaps
by establishing the first genetically engineered mouse model of DSRCT and to define its pathobiology
more fully by harnessing two recent novel observations in DSRCT, namely induction of neotranscripts
and recurrent ARID1A loss as a frequent additional genetic alteration in these cancers.
Aim 1: Developing a mouse model of DSCRT by germline and somatic genome editing. We will use the in
vivo somatic chromosomal engineering method pioneered by our laboratory (A.V.) to induce the
EWSR1-WT1 translocation in mice, based on co-expression of Cas9 and two gRNAs targeting the desired
translocation breakpoints. As p53 is mutated in approximately 10% of DSRCT cases, we will induce the
translocation concomitantly with p53 deletion in a cohort of mice to enhance tumor development.
Prompted by the recent finding that ARID1A mutations are commonly observed in DSRCT patients (see
Aim 3), we will also test the consequences of Arid1a loss on DSRCT initiation and progression in vivo.
Aim 2. Defining the landscape of EWSR1-WT1-associated neotranscripts in DSRCT. We (J.W., O.D.) have
recently reported that, in addition to dysregulating the expression of many target genes, oncogenic
fusions such as EWSR1-WT1 also drive the expression of completely novel sequences which we have
termed neotranscripts (J.W., O.D.). These are unannotated multi-exonic, polyadenylated RNAs not
expressed in any healthy tissue but directly induced by the altered localization patterns and co-factor
associations of the oncogenic fusion protein. A subset of neotranscripts are actively translated into
protein products, representing potential neoantigens. We will build upon our initial discovery of these
sequences and use them as a model system for dissecting EWSR1-WT1 mediated gene regulation as well
as determining what role these neotranscripts or their encoded proteins play in tumor biology.
Aim 3. Determining the role of recurrent ARID1A loss in DSRCT. While DSRCT displays one of the lowest
somatic mutation rates of any human solid cancer, intriguingly, inactivation of ARID1A, a subunit of the
canonical BAF complex, is the most common secondary mutation in DSRCT (about 6-12% of cases), being
more common than even TP53 alterations (M.L.). We propose to use isogenic models of ARID1A loss in
DSRCT cell lines to define the phenotypic and epigenetic effects of this recurrent secondary alteration in
DSCRT and use chemical and functional genomic screens to identify novel vulnerabilities associated with
ARID1A loss which may also yield more general insights into DSRCT pathobiology.

## Key facts

- **NIH application ID:** 10987961
- **Project number:** 1U01CA294124-01
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Marc Ladanyi
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $527,904
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10987961

## Citation

> US National Institutes of Health, RePORTER application 10987961, Desmoplastic small round cell tumor: harnessing new insights and new models (1U01CA294124-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10987961. Licensed CC0.

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