# TGF beta Pathway Inhibitors Rescue the Growth of Fanconi Anemia Primary Cells

> **NIH NIH P01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $433,367

## Abstract

PROJECT 2 PROJECT SUMMARY:
Fanconi Anemia (FA) is an inherited DNA repair disorder characterized by congenital abnormalities, cancer
predisposition, and progressive bone marrow failure. FA is caused by biallelic mutations in one of sixteen
FANC genes, the products of which cooperate in the FA/BRCA DNA repair pathway. Although the precise
biochemical functions of the FA/BRCA pathway remain unclear, the pathway promotes homologous
recombination (HR) repair. Due to the underlying DNA repair defect, FA cells are hypersensitive to genotoxic
DNA crosslinking agents. The mechanism of the bone marrow failure (BMF) in FA remains elusive. Our recent
studies suggest that BMF results, at least in part, from increased p53 expression in hematopoietic stem and
progenitor cells (HSCPs), leading to progressive cell cycle delay and apoptosis. BMF may also result from the
accumulation of DNA damage from the endogenous crosslinking agent, acetaldehyde, and the selective
toxicity of this agent to hematopoietic stem cells. Recently, we identified hyperactive TGFβ signaling as a
mechanism of bone marrow suppression in FA. Disruption of TGFβ signaling, through the use of shRNAs,
sgRNAs, and small molecule inhibitors confirmed the suppressive role of the pathway on FA cell growth. We
hypothesize that an upstream inhibitor of the TGFβ pathway (i.e., a monoclonal antibody to TGFβ itself) will
inhibit this pathway and rescue the function of the HSPCs, resulting in an increased probability of rescuing
bone marrow function in FA patients. It is possible that TGFβ inhibitors may also promote the clonal evolution
of premalignant or malignant hematopoietic stem cell. The specific aims of Project 2 are: 1) determine the
mechanism by which TGF-β inhibitors promote FA cellular growth and regulate DNA repair, 2) to determine
whether inhibition of TGF-β pathway rescues hematopoietic defects in FA mouse models, and 3) to determine
whether inhibition of TGF-β pathway rescues hematopoietic defects in primary bone marrow cells from FA
patients. Project 2 will interact extensively with Project 1 (Grompe), which will analyze other small molecules
capable of improving FA cell growth and Project 3 (Shimamura), which will analyze the effect of these small
molecules on primary human FA cells and will provide additional preclinical data for an FA clinical trial. The
projects will utilize four Core programs, as described in the accompanying Core components.

## Key facts

- **NIH application ID:** 9983803
- **Project number:** 5P01HL048546-25
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** ALAN D. D'ANDREA
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $433,367
- **Award type:** 5
- **Project period:** — → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983803

## Citation

> US National Institutes of Health, RePORTER application 9983803, TGF beta Pathway Inhibitors Rescue the Growth of Fanconi Anemia Primary Cells (5P01HL048546-25). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9983803. Licensed CC0.

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