# Drug susceptibilities in fusion oncogene-driven pediatric sarcomas

> **NIH NIH R21** · ROSWELL PARK CANCER INSTITUTE CORP · 2020 · $189,986

## Abstract

PROJECT DESCRIPTION
Synovial cell sarcoma (ScS) and Ewing's sarcoma (ES) are aggressive tumors with high mortality rates in
children and adolescents. These cancers are marked by well-established fusion oncogene drivers, SYT-
SSX1/2 for ScS and EWSR1-FLI1 for ES, yet because the fusion proteins encode transcriptional regulators
and not enzymes, these drivers are poor drug targets and these cancers are considered undruggable. The low
3-year survival rate of these patients, often under 50%, is associated with high incidences of systemic
metastatic disease which respond poorly to cytotoxic drugs. The use of histone deacetylate inhibitors (HDACi)
promises to increase survival based on targeting the oncogenic genes induced by the fusion oncogene
products. Yet, clinical trials with HDACi have had mixed results. Identification of shared drug-sensitive driver
pathways that act alone or in concert with HDACi will undoubtedly improve the survival of ScS and CCSST
patients. In Aim 1, we plan to identify testable ScS and ES drug sensitivities using a pipeline that combines
shRNA/CRISPRi synthetic lethality screening with bioinformatics programs that identify essentiality pathways
and cognate drug susceptibilities. We will develop a seamless work pipeline that incorporates i) deconvolution
analysis to match barcode (shRNA) or sgRNA clone hits with gene identification, ii) removal of general
essentiality genes, iii) optimized pathway identification from dropout gene lists, iv) identification of potential
drug candidates and v) in silico prioritization of drug candidates based on existing pharmacogenomic
databases. We will identify which essentiality pathways match those downregulated by HDACi, with the
assumption that the drugs that target HDACi-independent essentiality pathways might synergize with HDACi
against ScS and ES cells (Aim 1b). We will then test the ability of essentiality pathway drugs, alone or in
combination with clinically-relevant HDACi, to inhibit ScS and ES growth in vitro and in vivo (Aim 1c). In Aim
2, we will then analyze the transcriptome of clinical ScS samples to determine whether they share expression
of the druggable essentiality pathways identified in Aim 1. We will then attempt to develop patient organoid
cultures in order to test their sensitivity to pathway essentiality drugs from Aim 1, alone or in combination with
HDACi. Taken together, data from this project will allow us in future studies to develop preclinical therapeutic
studies, with the goal of increasing ScS and ES patient survival. Our success in this proposal will validate the
use of this screening/bioinformatics pipeline to identify drug sensitivities in other undruggable cancers,
especially those targeting pediatric populations.

## Key facts

- **NIH application ID:** 9965843
- **Project number:** 5R21CA235092-02
- **Recipient organization:** ROSWELL PARK CANCER INSTITUTE CORP
- **Principal Investigator:** IRWIN H. GELMAN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $189,986
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9965843

## Citation

> US National Institutes of Health, RePORTER application 9965843, Drug susceptibilities in fusion oncogene-driven pediatric sarcomas (5R21CA235092-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9965843. Licensed CC0.

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