# Disruption of Transcription Networks in Esophageal Adenocarcinoma Tumorigenesis

> **NIH NIH P01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2024 · $1,466,824

## Abstract

SUMMARY/ABSTRACT: The incidence of esophageal adenocarcinoma (EAC) has increased more than
six-fold over the past three decades. EAC patients' 5-year survival rate is less than 15%, underscoring the
need to understand the underlying biology to identify new therapeutic approaches. Chronic gastroesophageal
reflux disease (GERD), where acidic bile salts (ABS) abnormally refluxate into the esophagus, affects more
than 20% of the US population. In this program project, we hypothesize that interactions between APE1 redox
functions and isolevuglandins (IsoLGs) protein adducts promote activation and stability of critical oncogenic
transcription networks to mediate cell survival and expansion in esophageal tumorigenesis. This program
project leverages unique expertise of the principal investigators and takes advantage of advanced genetic and
surgical animal models, 3-dimensional in vitro models, human tissues, patient-derived xenografts (PDXs), and
innovative technologies. Project 1 investigates mechanisms by which APE1-redox function promotes
activation of SOX9 transcription factor in EACs under reflux conditions. Mechanistic and functional studies will
explore the role of APE1 redox function and IsoLGs adducts in regulating SOX9 to promote cancer cell survival
and expansion. Translational studies will determine the efficacy APE1 redox inhibitors using in vivo mouse
models. Project 2 investigates novel mechanisms of STAT3 by IsoLG protein adducts, as a cellular response
to oxidative stress induced by reflux conditions. The translational experiments include the use of isoLG
inhibitors to suppress formation of oncogenic protein adducts and progression to EAC in animal models of
Barrett’s tumorigenesis. Project 3 investigates the role SOX4 in EAC development. The translation studies in
Project 3 include testing FDA-approved drugs that inhibit SOX4, as a proof of concept to develop a novel
strategy to treat EACs. The integrated data exchange in this program project will enable us to collectively
investigate the role of APE1 redox functions and IsoLG protein adducts in esophageal tumorigenesis. The
three proposed cores deliver key services for all the projects. The Administrative Core (Core A) will manage
all scientific and fiscal issues and facilitate research interactions. The Molecular Pathology Core (CORE B)
will provide histopathology and immunohistochemistry services for animal and human tissues. The
Biostatistics and Bioinformatics Core (CORE C) will play a central role in providing computational,
statistical, and bioinformatics services. Via these Project and Core interactions we will identify biology-relevant
oncogenic molecular vulnerabilities that can be therapeutically targeted to benefit EAC patients

## Key facts

- **NIH application ID:** 10866608
- **Project number:** 5P01CA268991-03
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** WAEL EL-RIFAI
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,466,824
- **Award type:** 5
- **Project period:** 2022-07-08 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10866608

## Citation

> US National Institutes of Health, RePORTER application 10866608, Disruption of Transcription Networks in Esophageal Adenocarcinoma Tumorigenesis (5P01CA268991-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10866608. Licensed CC0.

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