The ARTI Center will test the central hypotheses that:
- Ferroptosis resistance is a key underlying mechanism for acquired radiation resistance, which can be targeted by ferroptosis-inducing agents.
- Ferroptosis plays a critical role in immunologic changes in the tumor microenvironment, which may serve as prognostic biomarkers for patient outcomes.
To achieve our overarching goals and to test these central hypotheses, we have formed three projects (including two basic/mechanistic research projects and one preclinical/translational research project) that are highly integrated and interactive.
These projects focus on crosstalks between ferroptosis and immune systems, interactions between ferroptosis and hypoxia, and hypoxia-immune system interactions.
- Project 1 (basic/mechanistic project) Ferroptosis resistance as a key driver in acquired radiation resistance will study ferroptosis resistance as a key driver in acquired radiation resistance in thoracic cancers and test the hypotheses that (1) ferroptosis resistance represents a key mechanism underlying acquired radiation resistance in lung and esophageal cancers, and (2) acquired radiation resistance in these cancers can be effectively overcome by combining FINs and immunotherapy. Leader: Boyi Gan, Ph.D.
- Project 2 (basic/mechanistic project) Tumor hypoxia promotes acquired resistance to radiation through ferroptosis inhibition will determine the extent to which tumor hypoxia promotes acquired resistance to radiation through ferroptosis inhibition, and test the hypotheses that (1) tumor hypoxia confers resistance to radiation-induced ferroptosis in lung and esophageal cancers, and (2) activating transcription factor 4 (ATF4) -induced solute carrier family 7 member 11 (SLC7A11) expression and hypoxia-inducible factors (HIF-1a, HIF-2a) play essential roles in determining sensitivity to ferroptosis induction. Leaders: Albert C. Koong, M.D., Ph.D. and Dadi Jiang, Ph.D.
- Project 3 (clinical/translational project) Role of genomic and microenvironment factors in conferring acquired resistance to ferroptosis to chemotherapy and radiation therapy in patients with esophageal cancer will determine the role of genomic and microenvironment factors in conferring ferroptosis resistance and acquired resistance to chemoradiation in esophageal adenocarcinoma. Leader: Steven H. Lin, M.D., Ph.D.
The Administrative Core will establish and manage the appropriate infrastructure (staff, advisory committee, and resources) needed to support the achievement of the ARTI Center’s aims in coordination with NCI program officials and in compliance with all institutional and NIH guidelines and policies. Leaders: Boyi Gan, Ph.D. and Albert C. Koong, M.D., Ph.D.
The Molecular Imaging Core will serve as a central clearinghouse for information and materials related to execution of molecular imaging, assist in transfection, cloning, and production of stable cell lines for imaging, and assist in imaging xenograft models and transgenic reporter mice. Leader: David R. Piwnica-Worms, M.D., Ph.D.