# Targeting transcriptional addiction in fusion-driven sarcoma

> **NIH NIH UM1** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $2,203,647

## Abstract

7. Project Summary/Abstract
The overarching goal of this NGC Center is to leverage expertise in small molecule drug discovery,
target identification, and protein and IDR biochemistry to identify and advance small molecules that
target transcriptional fusion oncoproteins by 1) targeting the transcriptional machinery that is co-opted
by fusion proteins to drive the oncogenic transcriptional programs, and 2) Directly impair IDR function
with small molecules.
 Transcriptional fusion proteins induce oncogenic gene expression programs that drive cancer
development and progression. These proteins act as neomorphic transcription factors by recruiting
and re-wiring transcriptional regulatory complexes. Rational drug design to directly target transcriptional
fusion proteins remains a major challenge because these proteins lack enzymatic activity and do not
have obvious pockets amenable for small molecule binding. In addition, the mechanisms by which
fusion oncoproteins co-opt transcriptional regulatory complexes are incompletely understood. As such,
the development of new therapies to target transcriptional fusion proteins has lagged efforts to develop
targeted therapies for mutant oncoproteins involved in cellular signaling.
 Our team has discovered that the Mediator transcriptional co-activator complex is co-opted to
control the oncogenic gene expression programs induced by transcriptional fusion proteins. We have
further identified the CDK8 kinase module as a druggable entry point by which to impair Mediator
function through a novel trapping mechanism. Our team will probe the biochemical and transcriptional
mechanisms through which CDK8/19 inhibitors alter Mediator function and develop CDK8/19 inhibitors
that maximize Mediator impairment and study these small molecules in advanced preclinical models of
Ewing sarcoma and rhabdomyosarcoma. We further identified that vaccinia-related kinase 1 (VRK1)
is a kinase that becomes synthetically lethal following CDK8/19 impairment, and our team will develop
novel specific VRK1 inhibitors and evaluate their efficacy in single agent and combination strategies.
 A central theme has recently emerged that many fusion proteins consist of a DNA binding
domain linked to an intrinsically disordered region (IDR). The IDR mediates self-association or phase
separation that has been shown to be essential for the oncogenic nature of these fusion proteins. Our
team has developed an innovative biochemical method of identifying the key protein regions within
IDRs that mediate self-association. We will map the key self-association residues in three fusion protein
IDRs and identify small molecules that impair the ability of these regions to drive phase separation.

## Key facts

- **NIH application ID:** 10987878
- **Project number:** 1UM1CA294119-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** David Glenn McFadden
- **Activity code:** UM1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,203,647
- **Award type:** 1
- **Project period:** 2024-07-08 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10987878

## Citation

> US National Institutes of Health, RePORTER application 10987878, Targeting transcriptional addiction in fusion-driven sarcoma (1UM1CA294119-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10987878. Licensed CC0.

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