# Characterizing Chromatin Remodeling Mechanisms of Chemo-Sensitivity and Resistance in Pediatric Solid Tumors

> **NIH NIH K00** · BOSTON CHILDREN'S HOSPITAL · 2024 · $114,533

## Abstract

PROJECT SUMMARY
Despite the known roles of chromatin remodeling complexes in driving more than 20% of human cancer, the
role of chromatin remodeling complexes in conferring therapeutic response in pediatric solid tumors is much
less understood. Rhabdoid tumor requires residual SWI/SNF activity for transformation and progression.
However, it is not known if SWI/SNF and its effect on the underlying epigenome is therapeutically targetable
and if a compound targeting this complex will be successful. Furthermore, SWI/SNF has been implicated in
epigenetic mechanisms of resistance suggesting this complex may be able to both confer sensitivity and
resistance depending on the cancer context. Fusion positive alveolar rhabdomyosarcoma (ARMS) gains
chemo-resistance without the simultaneous gain of mutations to drive this resistance. These data indicate
ARMS relapse may be driven by epigenetic mechanisms. Therefore, the overall objective of this study is to
define the role of chromatin structure in conferring therapeutic sensitivity in rhabdoid tumor (Aim 1) and
resistance in rhabdomyosarcoma (Aim 2).
I have identified mithramycin as a SWI/SNF inhibitor that induces epigenetic reprogramming and durable tumor
regression in rhabdoid tumor. A consequence of mithramycin treatment is amplification of H3K27me3, a novel
therapeutic vulnerability as well as the restoration of chemosensitivity. The overall goal of the F99 phase (Aim
1) is to identify synthetic lethalities that arise from SWI/SNF inhibition. Specifically, aim 1.1 will define inhibition
of H3K27me3 histone demethylases KDM6A/6B as a therapeutic vulnerability in rhabdoid tumor. Aim 1.2 will
define the mechanism of mithramycin-dependent chemosensitivity. These goals will build advanced expertise
in mechanistic pharmacology, high-throughput sequencing, and in vivo modeling of combination therapies. In
contrast to RT which is known to be chemo-refractory, alveolar rhabdomyosarcoma is initially responsive to
chemotherapy before gaining resistance. Therefore, the K00 phase of this fellowship (Aim 2) will define the
role of chromatin remodeling in fusion positive alveolar rhabdomyosarcoma therapeutic resistance (ARMS).
Aim 2.1 will identify the chromatin remodeler that coordinates with PAX3/7-FOXO1, the oncogenic
transcription factor that drives ARMS transformation and progression. Aim 2.2 will profile chromatin remodeling
during the establishment of chemoresistance in an established ARMS mouse model. This phase will expand
expertise in genomic approaches to include single-cell genomics and in vivo modeling to include transgenic
models.
In summary, this study addresses the need for a mechanistic investigation into the role of chromatin
remodeling in driving therapeutic response in pediatric solid tumors. Data and training acquired in this phase
will prepare me for a career exploring epigenetic mechanisms of therapeutic resistance in pediatric sarcomas.

## Key facts

- **NIH application ID:** 10884366
- **Project number:** 5K00CA253749-05
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Maggie Chasse
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $114,533
- **Award type:** 5
- **Project period:** 2021-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10884366

## Citation

> US National Institutes of Health, RePORTER application 10884366, Characterizing Chromatin Remodeling Mechanisms of Chemo-Sensitivity and Resistance in Pediatric Solid Tumors (5K00CA253749-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10884366. Licensed CC0.

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