# Minimizing the risk of therapy-related myeloid neoplasms by inhibiting genotoxic stress-induced expansion of leukemia-initiating cells with p53 mutations

> **NIH NIH R03** · DUKE UNIVERSITY · 2022 · $80,500

## Abstract

ABSTRACT
Due to an ever-increasing number of cancer survivors, myeloid neoplasms associated with
chemotherapy and/or ionizing radiation are a significant concern for public health. Clinical data indicate
that the outcome for patients with therapy-related myeloid neoplasms (t-MNs) is poor, with a 5-year
survival of 10%. The unfavorable response of t-MNs to standard cancer therapies is largely due to
mutations in the tumor suppressor p53. It has been demonstrated that p53 mutant t-MNs are developed
through the expansion of rare tumor-initiating cells harboring pre-existing p53 mutations. Therefore, the
overall goal of this project is to prevent the development of p53 mutant t-MNs by inhibiting the
expansion of tumor-initiating cells and/or by selectively killing tumor-initiating cells at the premalignant
stage. To selectively target p53 mutant cells, we will use APR-246, a small molecule drug in clinical
trials that reactivates mutant p53 protein by restoring wild-type p53 conformation and function. We
hypothesize that treatment with APR-246 will prevent the genotoxic stress-induced expansion of p53
mutant HSPCs and selectively kill p53 mutant HSPCs that have expanded after genotoxic therapies.
We will test this hypothesis using a novel mouse model that we have developed in which rare HSPCs
expressing a p53R172H mutation undergo cell expansion after exposure to total-body irradiation in two
specific aims: Aim 1 – Evaluate the impact of APR-246 treatment during total-body irradiation on the
expansion of p53 mutant HSPCs and Aim 2 – Examine the effect of APR-246 plus azacitidine on killing
p53 mutant HSPCs that have expanded after total-body irradiation. We anticipate that the outcomes
from this proof-of-concept R03 grant will generate reproducible data that support further investigation of
utilizing APR-246 or other mutant p53 activators to minimize the risk of t-MNs in cancer patients who
show clonal hematopoiesis of mutations in the tumor suppressor p53.

## Key facts

- **NIH application ID:** 10310505
- **Project number:** 5R03CA249562-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Chang-Lung Lee
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $80,500
- **Award type:** 5
- **Project period:** 2020-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10310505

## Citation

> US National Institutes of Health, RePORTER application 10310505, Minimizing the risk of therapy-related myeloid neoplasms by inhibiting genotoxic stress-induced expansion of leukemia-initiating cells with p53 mutations (5R03CA249562-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10310505. Licensed CC0.

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