# Project 1 - Molecular Determinants of Decitabine Responses.

> **NIH NIH P50** · WASHINGTON UNIVERSITY · 2020 · $346,707

## Abstract

Project Summary
The long-term goal of this project is to identify the patients with acute myeloid leukemia (AML) who are
the most likely to respond to decitabine therapy, and to determine the molecular mechanisms of
decitabine responses. We recently reported that TP53 mutated AML and MDS patients, which have a high
risk of relapse, and very poor outcomes, respond consistently to decitabine, a hypomethylating agent that can
be given as an outpatient, and which is well tolerated in most patients. However, most responding patients did
not have TP53 mutations, suggesting that other pathways can also influence decitabine sensitivity. The
molecular mechanisms associated with decitabine responses and subsequent relapse are currently unclear.
To refine and extend these findings, we propose the following specific aims:
Aim 1. We will determine the efficacy of decitabine salvage therapy in AML patients with TP53
mutations. Patients with relapsed/refractory AML and with TP53 mutations represent an ultra-high-risk
population with extremely poor outcomes, representing an unmet therapeutic need. We will therefore treat 60
relapsed/refractory AML patients known to have TP53 mutations with decitabine on days 1-10 of 28-day cycles
at 3 centers (Washington University, Fred Hutchinson Cancer Research Center, and the University of Iowa).
Responding patients will undergo allogeneic transplantation for consolidation therapy, if possible. We will
determine the overall survival at 1 year, as well as response rates, time to transplant, time to leukemia relapse,
and the average number of hospital days during cycles 1 and 2.
Aim 2. We will define the genomic and epigenomic signatures associated with decitabine responses.
We will use enhanced whole genome sequencing to determine whether TP53 wild-type patients have
recurrent, non-genic mutations, and whether recurrent mutations are acquired at relapse, regardless of TP53
status. We will integrate whole genome bisulfite sequencing with RNA-Seq to determine whether decitabine
causes specific and canonical patterns of DNA hypomethylation, whether these changes result in consistent
transcriptional signatures, and whether any of these patterns correlate with clinical outcomes.

## Key facts

- **NIH application ID:** 9961536
- **Project number:** 5P50CA171963-08
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Timothy J. Ley
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $346,707
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961536

## Citation

> US National Institutes of Health, RePORTER application 9961536, Project 1 - Molecular Determinants of Decitabine Responses. (5P50CA171963-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9961536. Licensed CC0.

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