# In Vivo Testing of Novel Drug Combinations for Pediatric Soft Tissue Sarcomas

> **NIH NIH U01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2021 · $767,363

## Abstract

PROJECT SUMMARY
Despite the advances made in our understanding of the etiology of pediatric soft tissue sarcomas
(STS), the overall survival of those diseases has not significantly improved in over 2 decades. For
children with recurrent disease, survival is below 30%, and long-term survivors have an increased
burden of disease associated with the curative therapies they received. Therefore, the goal of our
research team is to improve the survival and quality of life of children with STS by integrating basic,
translational, and clinical research. For the past 10 years, we have consented STS and other solid
tumor patients to donate tissue for orthotopic implantation into immunocompromised mice to develop
orthotopic patient derived xenografts (O-PDXs). Our O-PDXs have been used for ex vivo high-
throughput drug screening and in vivo testing using a standardized preclinical phase I, II, III paradigm.
Rhabdomyosarcoma (RMS) is the most common STS in children and genomic studies have shown that
rare subsets of clonally related cells can survive treatment and contribute to disease recurrence.
Subsequent integrated analyses using transcriptomic, epigenetic and proteomic data showed that RMS
tumors retain lineage-specific transcriptional and epigenetic signatures of their developmental origins.
More recently, single cell and single nucleus RNA-seq (sc/snRNA-seq) and in vivo lineage-tracing
showed that clones of cells can transition through their normal developmental programs. Indeed, single-
cell ATAC-seq demonstrated that the cell- and developmental stage–specific super-enhancer activity is
correlated with those clonal changes in gene expression. Chemotherapy eliminates the most
proliferative tumor cell populations, and the surviving dormant tumor cells rapidly expand and re-
establish their developmental hierarchy, which leads to disease recurrence. This is a striking example
of the complex cell-intrinsic and -extrinsic signaling within STS and the intricate connection between
developmental and oncogenic pathways in childhood cancer. In this proposal, we will perform in vivo
testing for 8-10 drugs per year using our STS O-PDX models. The most compelling pathways are
developmental kinase pathways (Aim 1), cell stress pathways (Aim 2) and G2/M cell cycle checkpoints
(Aim 3). Novel drug combinations will be tested as well as those that include conventional
chemotherapy for standard of care. Particular emphasis will be placed on eliminating all the clones in
the tumor to improve survival by reducing disease recurrence.

## Key facts

- **NIH application ID:** 10300360
- **Project number:** 1U01CA263969-01
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Michael A Dyer
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $767,363
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10300360

## Citation

> US National Institutes of Health, RePORTER application 10300360, In Vivo Testing of Novel Drug Combinations for Pediatric Soft Tissue Sarcomas (1U01CA263969-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10300360. Licensed CC0.

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