# New models and therapeutic approaches in alveolar rhabdomyosarcoma

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $385,444

## Abstract

PROJECT SUMMARY (30 lines)
Alveolar rhabdomyosarcoma (ARMS) is a common and aggressive muscle cancer that affects hundreds of
children annually in the United States. ARMS are pathognomonic with oncogenic chromosomal translocations
between the PAX genes and the fork-head transcription factor (FOXO1). Yet, the pathways that the PAX3/7-
FOXO1 transcription factors modulate, the tumor cells of origin, and the therapeutic vulnerabilities that arise in
ARMS cells is still unclear, largely due to lack of precision animal models that accurately recapitulate the same
translocation fusion events found in human ARMS. The long-term goal of our work is to uncover therapeutically
relevant pathways that drive ARMS growth. The overall objective of this application is to develop zebrafish
models of ARMS to identify therapeutic vulnerabilities that can be exploited clinically. Our central hypothesis is
that worse survival outcomes in PAX3-FOXO1+ ARMS are reflected in differences in cells of origin, elevated
numbers of molecular defined tumor-propagating cells (TPCs), and predisposition to metastasis. The feasibility
of our approach is supported by our work in using zebrafish to model a wide range of human cancers, recent
optimization of Crispr/CAS9 approaches to create patient-specific translocations using CRE/Lox, and our
successful high-content imaging screening approach to identify FDA approved drugs with efficacy in curbing
growth of other RMS subtypes. The rationale for our research is that there are few good experimental animal
models that accurately mimic the underlying genetics of human ARMS, obviating our ability to define how
specific oncogenic fusions drive cancer growth. This work is significant because it will uncover divergent
cellular mechanisms that account for differences in the clinical manifestation of PAX3/7-FOXO1+ ARMS,
identify new therapies to treat ARMS, and provide new modeling approaches for translocation+ cancers, all
expressed goals outlined in PA-16-251 supported by the Cancer Moonshot Initiative. Aim 1 will characterize
differences in PAX3/7-FOXO1-induced ARMS using innovative zebrafish models, testing our hypothesis that
fusion+ ARMS have inherent differences in proliferation and cell(s)-of-origin. Aim 2 will assess PAX3/7-FRKH
for differential effects on modulating metastasis and tumor propagating potential, testing our hypothesis that
PAX3-FOXO1+ ARMS do worse clinically because they have elevated TPC numbers and metastatic capacity.
Aim 3 will use an innovative high-content imaging screen to identify FDA-approved drugs that kill TPCs and
suppress growth of human ARMS. With respect to outcomes, our research will develop much-needed precision
animals models of ARMS and identify key differences in PAX3/7-FOXO1+ ARMS including likely differences in
cell-of-origin, TPCs, and metastatic capacity, providing explanation of why PAX3-FOXO1+ ARMS do worse
clinically. Our work will also identify novel therapies to kill TPCs in human patient d...

## Key facts

- **NIH application ID:** 10128407
- **Project number:** 5R01CA226926-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** David Michael Langenau
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,444
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128407

## Citation

> US National Institutes of Health, RePORTER application 10128407, New models and therapeutic approaches in alveolar rhabdomyosarcoma (5R01CA226926-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10128407. Licensed CC0.

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