# Reprogramming myogenic regulatory factors in RMS to promote differentiation and halt growth

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $627,696

## Abstract

Summary
Rhabdomyosarcoma (RMS) accounts for 3-4% of all pediatric cancers, with less than a 30% overall 5-year survival
rate for children diagnosed with metastatic RMS. Sarcoma patients also experience higher rates of morbidity and
mortality than other cancer patients, and this is particularly evident in children. As a result of their therapies, 42%
of childhood cancer survivors experience severe, disabling, or life threatening conditions, including secondary
tumors. Thus, there is clearly a need to develop new, more targeted treatment strategies for pediatric tumors
such as RMS; treatments that inhibit tumor progression yet confer limited side effects. In many cancers,
embryonic programs, including the acquisition of stem/progenitor states, are instituted to contribute to tumor
progression. Such reinstatement or retention of developmental programs may be a key driving factor in
Embryonal Rhabdomyosarcoma (ERMS, which are generally fusion negative and also referred to as FN-RMS).
In RMS, high expression of myogenic-lineage transcription factors (TF), MYOD1 and MYOG, is observed.
However, despite high expression of these TFs, RMS cells fail to differentiate. Instead, these TFs drive the RMS
malignant phenotype, since knockout of these MRFs results in lethality to the RMS cell. Thus, a key unanswered
question in the field is why and how the myogenic regulatory factors (MRFs) depart from their canonical roles as
drivers of muscle differentiation to instead maintain RMS cells in an undifferentiated state. In this proposal, we
are examining whether SIX1, a critical TF that regulates muscle development, is responsible for globally altering
the function of MRFs. Our data show that elevated SIX1 expression promotes FN-RMS progression and growth
by promoting an RMS progenitor-like state. Intriguingly, SIX1 knockdown induces a muscle differentiation
signature, concomitant with re-localization of key MRFs genome-wide. These data suggest that in FN-RMS, SIX1
overexpression alters MRF function, promoting an RMS progenitor-like phenotype and enhancing tumor growth
and progression. Thus, in this proposal we will test the following hypothesis: SIX1 and its obligate cofactors
EYA2/3 cooperatively drive the progression of FN-RMS by altering the genomic landscape, causing MRFs
to favor growth over differentiation. Since SIX1 expression in differentiated tissues is low, targeting it may
therefore be a means to inhibit FN-RMS with limited side effects to untransformed cells where SIX1 is
dispensable. Specific aims are as follows: 1) To determine the molecular mechanism by which SIX1 serves as
a master regulator of the muscle progenitor vs differentiated state in development and in RMS. 2) To identify the
critical SIX1 cofactors (with a focus on EYA proteins) that, when targeted, can induce differentiation and inhibit
RMS growth. This work will take advantage of normal developmental regulatory mechanisms to inhibit the tumor,
and thus may have limited toxicity due to ...

## Key facts

- **NIH application ID:** 10842290
- **Project number:** 5R01CA275187-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Kristin Artinger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $627,696
- **Award type:** 5
- **Project period:** 2023-05-16 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842290

## Citation

> US National Institutes of Health, RePORTER application 10842290, Reprogramming myogenic regulatory factors in RMS to promote differentiation and halt growth (5R01CA275187-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10842290. Licensed CC0.

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