# Developing differentiation therapy for the treatment of patients with acute myeloid leukemia

> **NIH NIH K08** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $169,268

## Abstract

Project Summary
The goal of this project is to develop new, effective, and well-tolerated differentiation therapy for the treatment
of patients with acute myeloid leukemia (AML).
Despite remarkable advances in understanding the genomic underpinnings of AML, patients still receive the
same chemotherapy that they did forty years ago. The study that established the combination of cytarabine
and an anthracycline as standard chemotherapy was published in 1973(!). Immunotherapy, and novel target
mutations (e.g. IDH, Flt3-ITD, Dot1L) raise the possibility of better therapies for well-defined patient sub-
populations. However, differentiation therapy holds the potential of being more globally applicable for
leukemias with a wide variety of underlying mutations. The finding that HoxA9 is overexpressed in 70% of AML
prompted us to establish a phenotypic screening system to identify small molecules that could overcome the
differentiation block established by HoxA9.
A high-throughput flow-cytometry differentiation screen, followed by the molecular analysis of compound-
resistant cell lines, led to the identification of the enzyme dihydroorotate dehydrogenase (DHODH) as the
target of specific inhibitors that could trigger myeloid differentiation. DHODH, and its role in regulating the pool
of intracellular uridine, is a novel target in AML. This unexpected in vitro finding in our engineered cell line was
confirmed in human cell lines and in ex vivo PDX models of AML. We have since demonstrated that DHODH
inhibitors are highly active in vivo in murine syngeneic leukemia models, human xenograft models, and PDX
models of AML.
This application proposes to determine the molecular mechanism through which the depletion of intracellular
uridine results in myeloid differentiation. We have outlined a series of studies that build on preliminary data
showing the existence of a clear therapeutic window between normal hematopoietic stem cells and leukemic
cells in terms of their ability to survive periods of uridine starvation. While arguably ambitious, the proposed
experiments take advantage of completed preliminary studies, allowing us to query the effect of DHODH
inhibition in multiple model systems. In particular, the profiling of a 300+ panel of cell lines has yielded lines
that are sensitive and lines that are 1000x more resistant to DHODH inhibition. Understanding the basis of this
striking phenotype has both basic science and immediate clinical implications in terms of patient selection and
disease indication.
Understanding the link between pyrimidine biosynthesis and myeloid differentiation will advance our
understanding of normal myelopoiesis and of how differentiation is dysregulated in the setting of leukemia. The
ready availability of potent inhibitors of DHODH with favorable pharmacokinetic properties raises the exciting
possibility of rapid clinical translation.
David Sykes is a post-doctoral fellow in Dr. David Scadden’s laboratory at the Massachusetts Gener...

## Key facts

- **NIH application ID:** 9914232
- **Project number:** 5K08CA201640-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** David B Sykes
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $169,268
- **Award type:** 5
- **Project period:** 2017-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9914232

## Citation

> US National Institutes of Health, RePORTER application 9914232, Developing differentiation therapy for the treatment of patients with acute myeloid leukemia (5K08CA201640-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9914232. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*