# Epigenetic and Genetic Vulnerabilities in Synovial Sarcoma

> **NIH NIH P50** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $344,657

## Abstract

ABSTRACT 
RP-4 focuses on synovial sarcoma, an aggressive pediatric/young adult sarcoma driven by the SS18-SSX 
fusion oncogene. SS18-SSX has emerged as a multi-faceted disruptor of epigenetic control that mediates 
genome-wide transcriptional deregulation, resulting in proliferation and aberrant or arrested 
differentiation. Our overall goal is to probe the basic pathobiology of synovial sarcoma so as to nominate 
potential therapeutic targets. We propose hypothesis-driven screening approaches, namely functional 
genomic screens to uncover vulnerabilities among chromatin/transcriptional regulators and among 
kinases, as well as targeting the oncogenic fusion itself. Based on the hypothesis that SS18-SSX causes 
synovial sarcoma cells to possess special “epigenetic” dependencies, we will, in Aim 1, (a) perform a broad 
functional genomic screen using a new CRISPR knock-out pooled library against epigenetic modulators; 
and (b) seek to further validate and understand mechanistically KDM2B, a dependency identified in 
preliminary studies, as a vulnerability in human synovial sarcoma cells. Based on the hypothesis that 
another effect of SS18-SSX is transcriptional deregulation of growth signaling, Aim 2 will employ three 
orthogonal strategies to better define targetable kinase vulnerabilities in this sarcoma. Specifically, we will 
(a) perform a CRISPR-based functional genomic screen against kinases in human synovial sarcoma cell 
lines; (b) identify activated kinases in synovial sarcoma by phospho-protein profiling of patient-derived 
xenografts; and (c) define the targets of pazopanib in synovial sarcoma by two complementary methods, 
affinity proteomics and PLATO (parallel analysis of translated ORFs). These two analyses should clarify the 
critical kinase targets of this multi-targeted kinase inhibitor that is active in a subset of synovial sarcoma 
patients. The results generated in this Aim will be integrated to form the basis for more rational targeting of 
critical kinases in this sarcoma. As SS18-SSX is the primary driver oncogene in synovial sarcoma, the 
junction point of the fusion transcript represents an rational and highly specific target for sequence-based 
therapeutics using new antisense oligonucleotide (ASO) approaches. Building on our promising results 
using gapmer ASOs to directly target other sarcoma fusions in vitro and in vivo, we will optimize and 
evaluate gapmer ASOs against SS18-SSX. In Aim 4, we will validate the targets identified in Aims 1-3 by 
confirming on-target effects and expression in human tumors, and we will perform preclinical evaluation of 
their potential as therapeutic targets in vitro and in vivo. The most promising targets will be validated and 
subjected to extensive preclinical evaluation using multiple, orthogonal, relevant in vitro and in vivo 
systems. The ultimate overall goal of this fundamentally translational project is to begin clinical evaluation 
of at least one agent based on the novel ta...

## Key facts

- **NIH application ID:** 10247701
- **Project number:** 5P50CA217694-04
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Marc Ladanyi
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $344,657
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247701

## Citation

> US National Institutes of Health, RePORTER application 10247701, Epigenetic and Genetic Vulnerabilities in Synovial Sarcoma (5P50CA217694-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10247701. Licensed CC0.

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