# Elucidating the survival mechanisms of rhabdomyosarcoma

> **NIH NIH F30** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2022 · $48,903

## Abstract

PROJECT SUMMARY/ABSTRACT
Rhabdomyosarcoma (RMS) is the most common soft tissue cancers affecting children. Despite aggressive
combinatorial therapy, nearly 30% of children diagnosed with RMS will succumb to either metastasis or
recurrence. While RMS can occur anywhere in the body, all cases are defined by the expression of skeletal
muscle markers. Skeletal muscle differentiation is controlled by a family of four DNA binding myogenic regulatory
factors - MyoD, Myf5, myogenin and MRF4. The prevailing belief is that RMS tumor cells are unable to complete
differentiation due to the dysfunction of these myogenic factors. Our laboratory previously showed that NF-κB
contributes to RMS by maintaining tumor cells in an undifferentiated state. Interestingly, even though NF-κB is
widely known to function in cancer as a survival factor, RMS appears to be unique in not needing NF-κB to
overcome stress-induced apoptosis. Instead, we find that MyoD is able to compensate for NF-κB. One
mechanism by which MyoD promotes survival is by keeping RMS cells in a partially differentiated state. Another
mechanism, which we elucidated through a series of transcriptomic and bioinformatic analyses, indicates that
MyoD is capable of suppressing apoptotic genes. Unique to this latter mechanism is that suppression requires
promoter methylation. Based on these data, I hypothesize that MyoD functions in RMS by acting as an oncogene
to promote cell survival, which occurs by 1) maintaining RMS cells in a partially differentiated state and 2)
suppressing apoptotic genes through the regulation of DNMTs and promoter hypermethylation. The second part
of this hypothesis will be explored in this proposal through two aims. In Aim 1, I plan to characterize the pro-
apoptotic genes suppressed by MyoD and their relevance in RMS. I will accomplish this through gain and loss
of function studies for each gene and observing the death response phenotype. I will also explore the methylation
of the gene promoters in response to MyoD expression or treatment with compounds that regulate methylation.
In Aim 2, I will perform preclinical studies to test the efficacy of demethylation agents as a therapeutic strategy
in RMS. Both in vitro and xenograft tumor studies will be utilized, using demethylation agents alone or in
combination with RMS standard of care drugs. The impact of my findings might not only demonstrate a novel
role of MyoD in RMS, but might also advance novel therapeutic strategy for the treatment of RMS patients.

## Key facts

- **NIH application ID:** 10464404
- **Project number:** 1F30CA265071-01A1
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Alexander R. Oles
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $48,903
- **Award type:** 1
- **Project period:** 2022-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464404

## Citation

> US National Institutes of Health, RePORTER application 10464404, Elucidating the survival mechanisms of rhabdomyosarcoma (1F30CA265071-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10464404. Licensed CC0.

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