# Tumor hypoxia promotes acquired resistance to radiation through ferroptosis inhibition

> **NIH NIH U54** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $275,188

## Abstract

Project 2 Summary
Tumor hypoxia, defined as low intratumoral oxygen tension, is common to most solid malignancies, including
lung and esophageal cancer. Lung and esophageal cancer treatments include radiation therapy (RT); however,
clinically, these cancers develop acquired resistance to RT. The mechanisms of acquired resistance to RT are
unknown but may involve a type of cell death called ferroptosis, which is the overarching theme of the proposed
Acquired Resistance to Therapy and Iron (ARTI) Center. Project 2 will contribute to this overarching theme
by determining whether hypoxia drives ferroptosis resistance, thereby promoting the acquired resistance to RT.
Project 2 will utilize lung and esophageal cancer cell lines generated in Project 1 that are deficient in the
ferroptosis resistance-mediator Solute Carrier Family 7 Member 11 (SLC7A11) and one of its transcription
factors: activating transcription factor 4 (ATF4). The transcription of genes, including hypoxia-related genes, may
be dynamically regulated within tumor cells and cells of the tumor microenvironment during chemoradiation
therapy (CRT) of esophageal adenocarcinoma, which is a focus of Project 3. In order to determine whether
oxygen is required for ferroptosis induction by RT, lung and esophageal cancer cells will be subjected to varying
oxygen concentrations and radiosensitivity, lipid peroxidation (i.e., driver of ferroptosis), and SLC7A11
expression will be measured (Aim 1). Aim 2 will focus on the delineation of the mechanisms of hypoxia-driven
ferroptosis resistance during acquired RT resistance by determining whether SLC7A11 expression is dependent
on ATF4 under hypoxic conditions during RT. Furthermore, as hypoxia inducible factors (HIFs) have been shown
to promote radioresistance, the effect of hypoxia-induced HIF activation in acquired resistance to ferroptosis will
be investigated. To test the hypothesis that enhanced tumor oxygenation through hyperbaric oxygen treatment
(HBOT) as well as small molecule HIF and ATF4 inhibitors can overcome acquired radioresistance by enhancing
ferroptosis induction, lung tumor and esophageal tumor xenografts in mice will be treated with RT in combination
with HBOT or HIF/ATF4inhibitors(Aim 3). Tumor growth after RT will be monitored with weekly noninvasive
bioluminescence imaging at the Molecular Imaging Core (MIC). Furthermore, in the MIC, hypoxic regions within
tumors will be monitored in real-time by performing positron emission tomography (PET) using the PET tracer
18F-Fluoroazomycin arabinoside (FAZA). Overall, the differential regulation of ferroptosis and acquired RT
resistance by poorly oxygenated and well oxygenated areas in tumors discovered in Project 2 will iteratively
strengthen and support the basic science/mechanistic Project 1 and the preclinical/translational Project 3 by
helping identify tumor regions that may develop acquired resistance to RT that could aid in patient selection for
subsequent treatments.

## Key facts

- **NIH application ID:** 10917382
- **Project number:** 5U54CA274220-03
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** ALBERT KOONG
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $275,188
- **Award type:** 5
- **Project period:** 2022-09-20 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10917382

## Citation

> US National Institutes of Health, RePORTER application 10917382, Tumor hypoxia promotes acquired resistance to radiation through ferroptosis inhibition (5U54CA274220-03). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10917382. Licensed CC0.

---

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