# SUMOylation disruption is toxic for SS18-SSX-driven synovial sarcoma

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $525,001

## Abstract

Project Summary:
Synovial Sarcoma (SS) is driven by the SS18-SSX oncofusion, and SS18-SSX is the only reoccurring mutation
in SS. SS normally metastasizes, resulting in a 15-year overall survival rate of less than 50%. This presents a
particular problem as 1/3 of the patients that are diagnosed are under the age of 30. Polychemotherapy has a
modest and variable effect on patients, immunotherapy activity is unremarkable, and there are currently no
targeted therapy options to combat SS. SS18-SSX remains undruggable despite clearly being the driving event
in these cancers. Thus, SS requires entirely new therapeutic approaches. In light of this, we tried to identify
potential novel therapies by assessment of full genome short-interfering (si)-RNA screen data deposited into the
DepMap database and subsequent cell culture experiments with SS cell lines and patient-derived xenograft cell
cultures. Through these efforts, we have identified a clinically actionable synthetic lethality with SSX-SS18 in SS,
namely disruption of the post-translational modification, SUMOylation. We find SS18-SSX activates the
SUMOylation, and disruption of this pathway with the in-clinic SUMOylation inhibitor, TAK-981, disrupts SS18-
SSX function, induces DNA damage and shrinks SS tumors in mice.
Specific Aims
Specific Aim 1: Test a diverse set of synovial sarcoma mouse models for efficacy and safety of SUMOylation
inhibition
Specific Aim 2: Investigate the relationship between SS18-SSX and the SUMOylated proteome in synovial
sarcoma
Study Design: We will further characterize the sensitivity of TAK-981 (alone and with chemotherapy and BRD9
degrader) in SS cell culture models including patient-derived organoids, and in vivo, in orthotopic patient-derived
xenograft (PDX) models and genetic mouse models of SS. Through a series of proteomic and biochemical
experiments, we will further categorize the mechanism of SS18-SSX-dependent toxicity stemming from
disruption of the SUMOylation pathway. We will further examine the role of SS18-SSX in activating the
SUMOylation pathway and the mechanism of action of TAK-981 in SS, which involves disrupting the SS18-SSX-
ncBAF transcriptome. In all, we will attempt to gather the preclinical evidence supporting the translation of
SUMOylation inhibitors to treat SS.

## Key facts

- **NIH application ID:** 10897929
- **Project number:** 5R01CA272710-02
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Anthony Charles Faber
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $525,001
- **Award type:** 5
- **Project period:** 2023-08-02 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10897929

## Citation

> US National Institutes of Health, RePORTER application 10897929, SUMOylation disruption is toxic for SS18-SSX-driven synovial sarcoma (5R01CA272710-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10897929. Licensed CC0.

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