# The Utility of WDR5 WIN Site Inhibitors in Rhabdoid Tumors

> **NIH NIH F31** · VANDERBILT UNIVERSITY · 2022 · $10,238

## Abstract

PROJECT SUMMARY/ABSTRACT
Rhabdoid tumors (RT) are rare and aggressive childhood cancers with exceptionally high rates of mortality.
Most children suffering with RT will die within 18 months of diagnosis. There is currently no standard of care
for these children and—with fewer than 25 cases of RT diagnosed in the U.S. each year—the likelihood of
developing new treatment strategies for this cancer are low. Despite its aggressive characteristics, however,
RT has an unusually simple genetic profile in that it is driven by loss of a single gene, SMARCB1, which
encodes the SNF5 component of the SWI/SNF chromatin remodeling complex. Recent work has shown that
SNF5 loss leads to RT, in part, by activating MYC, an oncoprotein transcription factor with extensive pro-
tumorigenic functions. By extension, anti-MYC therapies could have immense value in treating RT. But MYC
itself is widely considered to be undruggable, meaning that pharmacological strategies to target MYC, if
successful, will most likely focus on the co-factors MYC uses to function. A MYC cofactor for which inhibitors
are being developed is WDR5, which facilitates the recruitment of MYC to chromatin at "protein synthesis
genes" (PSGs) that stimulate biomass accumulation, a critical part of the oncogenic repertoire of MYC.
Importantly, genetic disruption of the WDR5-MYC interaction decreases transcription of PSGs and promotes
tumor regression in vivo. WDR5 "WIN site" inhibitors quickly and comprehensively displace WDR5 from
chromatin and as a result, selectively reduce MYC levels at PSGs. These findings predict that WIN site
inhibitors could also be used for treating RT. The goal of this project is to understand the response of RT cells
to WIN site inhibitors and to identify important modulators conferring sensitivity or resistance. To characterize
the response to WIN site inhibition in RT cells, Specific Aim 1 will combine genomic and cellular approaches
to identify changes in WDR5 and MYC chromatin association and in transcription to inform mechanisms by
which WIN site inhibitors promote growth inhibition and cell death in RT cells. In Specific Aim 2, whole
genome CRIPSR screens and synergy screens will define genes that confer sensitivity or resistance and
identify drugs that improve the efficacy of WIN site inhibitors. Completion of this work will uncover how RT
cells respond to WIN site blockade and inform new treatment strategies for RT and potentially other MYC-
driven tumors. The combination of a rigorous research project, an exceptional mentor, and the stimulating
research environment at Vanderbilt will yield an outstanding training experience. The project and training plan
detailed in this proposal will equip me with the tools to become an impactful independent cancer researcher.

## Key facts

- **NIH application ID:** 10328250
- **Project number:** 5F31CA257102-02
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Andrea Wojciechowski
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $10,238
- **Award type:** 5
- **Project period:** 2021-02-01 → 2022-05-13

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10328250

## Citation

> US National Institutes of Health, RePORTER application 10328250, The Utility of WDR5 WIN Site Inhibitors in Rhabdoid Tumors (5F31CA257102-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10328250. Licensed CC0.

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