# Metabolic targeting of heterogenous myelodysplastic syndrome stem cells

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $402,556

## Abstract

PROJECT SUMMARY/ABSTRACT
The goal of this project is to define vulnerabilities that can be leveraged to comprehensively eradicate MDS stem
cells (MDS-SCs). This objective is based on the concept that MDS-SCs lie at the root of disease and are not
effectively targeted by current therapies. A significant challenge in achieving this goal is the heterogeneity of the
MDS-SC population, as recent studies have identified distinct subsets of MDS-SC with varying responsiveness
to therapy. Thus, the premise of our work is that understanding and targeting the unique properties of
heterogenous MDS-SCs is critical to improve outcomes in MDS. The foundation of our project is built upon
laboratory studies coupled with an active clinical trial (NCT03564873) evaluating the clinical impact of targeting
protein synthesis with the global translation inhibitor omacetaxine (oma) in MDS-SC from individuals with high-
risk MDS. While the results from our trial using oma in combination with the hypomethylating agent azacytidine
(aza) are indeed promising and represent a substantial improvement over standard of care (aza alone), instances
of disease progression in patients suggest oma may not eradicate all MDS-SC subsets. These outcomes,
alongside toxicities associated with global protein translation inhibition have motivated us to better characterize
the unique biological and functional properties of heterogenous MDS-SC subsets. With the goal of developing
next-generation approaches that more effectively target MDS-SC while minimizing dose-limiting toxicities to
patients, here we will address two primary questions: 1) what is the overall efficacy of protein synthesis inhibition
amongst varying MDS-SC subtypes, 2) what are the optimal therapeutic strategies to eradicate MDS-SC based
on their sensitivity to protein synthesis inhibition? Hence, we will leverage comprehensive CITE-seq based
analyses of serial pre- and post-treatment specimens from our oma/aza clinical trial alongside PDX-based
functional studies to identify the link(s) between features such as protein synthesis activity, MDS-SC genotype
and clonal behavior with oma response at single cell resolution. We will define the mechanisms governing
reliance on protein synthesis in MDS-SC, focusing on pharmacological and molecular genetic-based targeting
of key pathways linked with oma sensitivity. Lastly, we will develop improved approaches to comprehensively
target heterogenous MDS-SC populations, with focus on next-generation strategies that more selectively target
aberrant metabolic features of MDS-SC uncovered by our ongoing CITE-seq characterization of patient
specimens. Taken together, the proposed studies will use advanced functional models and single-cell resolution
analyses to identify key vulnerabilities of MDS-SC that can be leveraged to design rational therapeutic
approaches to improve outcomes for MDS patients.

## Key facts

- **NIH application ID:** 10931676
- **Project number:** 5R01CA286717-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Eric M Pietras
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $402,556
- **Award type:** 5
- **Project period:** 2023-09-19 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931676

## Citation

> US National Institutes of Health, RePORTER application 10931676, Metabolic targeting of heterogenous myelodysplastic syndrome stem cells (5R01CA286717-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10931676. Licensed CC0.

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