Approximately 50% of cancer patients receive radiation therapy (RT), but local recurrence still occurs in 30-50% of cases due to the development of RT resistance. This issue is particularly significant in patients with locally advanced thoracic cancers, such as lung and esophageal cancers. While RT can induce ferroptosis, an iron-dependent form of cell death, it is unclear whether tumors develop resistance to ferroptosis, contributing to RT resistance. This is the central focus of the proposed Acquired Resistance to Therapy and Iron (ARTI) Center.
The ARTI Center aims to:
1.
Bridge the basic science mechanisms of ferroptosis in acquired resistance with translational research in preclinical models and human patient samples.
2.
Identify cohorts of patients who are at greatest risk to develop acquired RT resistance.
3.
Investigate the ability of novel therapeutic agents to re-sensitize lung and esophageal cancer cells to radiation by inducing ferroptosis.
Ferroptosis Mediates Radio-therapy-induced Cancer Cell Death and Tumor Suppression
The ARTI Center includes two basic research projects (Project 1 and Project 2), one preclinical/translational project (Project 3), and a Molecular Imaging Core (MIC).
Project 1 will investigate whether avoiding ferroptosis is a key factor in acquired RT resistance, using radioresistant lung and esophageal cancer cell lines and xenograft models, which will also be used in Project 2.
Project 2 will test the idea that hypoxia, a known driver of tumor radio-resistance, suppresses ferroptosis during RT and contributes to acquired RT resistance. It will also analyze hypoxia-related genes and other targets of RT resistance using single-cell sequencing.
Project 3 will study immune cell changes in the tumor microenvironment of humanized tumor models from patients with esophageal adenocarcinoma who responded or did not respond to chemoradiation therapy. These changes might serve as biomarkers for predicting RT resistance and patient outcomes and could be influenced by the ferroptosis-inducing agents tested in Projects 1 and 2.
The Molecular Imaging Core (MIC) will support these projects by using bioluminescence imaging to monitor tumor growth, PET tracers to identify cystine transporter activity and hypoxic regions within tumors, and innovative PET tracers for detecting activated immune cells. The ARTI Center will also establish an Administrative Core to ensure effective communication and collaboration between project leaders, the NCI and ARTNet program staff, and other ARTNet centers.
Overarching Theme: Inducing ferroptosis as a therapeutic strategy to overcome acquired radio-resistance
The Principal Investigators of the ARTI Center are Drs. Boyi Gan and Albert Koong.
(For additional information, please visit NIH RePORTER and ARTI Center web portal)
