# Preclinical Studies of Marrow Failure and Clonal Evolution in Fanconi Anemia

> **NIH NIH P01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $499,509

## Abstract

Project 3 Summary
Fanconi anemia (FA) is a recessively inherited syndrome characterized by bone marrow failure, cancer
predisposition, and congenital anomalies. FA is a genetically heterogeneous disorder caused by mutations in
any of 16 genes which function coordinately to promote DNA repair and prevent apoptosis in response to
inflammatory cytokines. Treatment options for marrow failure in FA include androgens and hematopoietic stem
cell transplant, but clinical outcomes have been limited by treatment-related toxicities. To address this
challenge, this project will investigate and develop alternative medical therapies with greater efficacy and
reduced side effects. The mechanism of action of therapeutic agents carries profound implications for FA
patient prognosis. Agents that block adaptive stress responses to DNA damage may improve marrow failure
but at the risk of promoting the survival of genetically damaged cells which may increase the risk of clonal
evolution. Our hypothesis is that compounds that rescue hematopoiesis by protecting from DNA damage
provide opportunities to develop safer and more effective therapies to treat marrow failure in Fanconi anemia.
The prior funding period of this program project resulted in the identification of several small molecule
compounds that improve growth and hematopoiesis in murine models and immortalized cell lines. The
molecular mechanism(s) whereby these compounds rescue FA cells will be investigated in Project 1 (PI: Dr.
Grompe) and Project 2 (PI: Dr. D'Andrea). Project 3 focuses on evaluating these compounds in primary FA
bone marrow cells and FA induced pleuripotent stem cell (iPSC) models (Aim 1) to investigate their effects on
hematopoiesis, DNA damage, DNA repair response, and clonal outgrowth. Compounds that rescue
hematopoiesis by reducing DNA damage will be prioritized for clinical trial development in Aim 2. Potential
biomarkers of DNA damage will be developed for correlative biological studies within the clinical trial. The
successful completion with these aims will yield a clinical trial protocol and associated regulatory documents
ready to implement by the completion of this project. These agents may be broadly applicable for the
treatment of marrow failure in general.

## Key facts

- **NIH application ID:** 9983804
- **Project number:** 5P01HL048546-25
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Akiko Shimamura
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $499,509
- **Award type:** 5
- **Project period:** — → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983804

## Citation

> US National Institutes of Health, RePORTER application 9983804, Preclinical Studies of Marrow Failure and Clonal Evolution in Fanconi Anemia (5P01HL048546-25). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9983804. Licensed CC0.

---

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