Program in Cancer Biology

Radiation induced lung injury is a crucial dose-limiting factor in patients receiving thoracic radiotherapy, affecting a significant proportion of patients even with use of newer radiotherapy techniques. The James West and Freeman Laboratories are investigating a novel pathway regulating fibroblast activation that can be directly targeted to limit progressive radiation-induced lung fibrosis. We found that the thromboxane-prostanoid receptor (TPr) was constitutively expressed in human and murine fibrotic pulmonary fibroblasts and that pharmacological inhibition or conditional genetic ablation of the TPr markedly attenuated pulmonary fibrosis in mice resulting from ionizing radiation. Although thromboxane A2 is a major ligand for TPr, we found that TPr signaling was being driven by F2-isoprostanes (F2-IsoPs), resulting from non-enzymatic, free-radical oxidation of arachidonic acid. We have demonstrated that ionizing radiation induces F2-IsoP generation in cell culture and in murine pulmonary tissue in vivo. F2-IsoPs are increased in idiopathic pulmonary fibrosis due to oxidative stress in this disease, but whether they are increased in patients who develop radiation-induced pulmonary fibrosis (RIPF) is unknown, although preclinical and clinical studies provide key support for the overall hypothesis that non-enzymatic free radical-induced oxidation of arachidonic acid signaling significantly contributes to RIPF. There are key gaps in our knowledge that need to be filled before a clinical trial targeting this pathway would be appropriate. First, the therapy would need to work in the context of existing standard of care, including immune checkpoint therapy. Second, although it is likely that there is an increase in either thromboxane or F2-IsoPs in RIPF, we need to verify that patients receiving thoracic radiation actually show an increase in one or more of these molecules. Finally, we need a better understanding of the mechanism by which TPr regulates pulmonary myofibroblast differentiation and activation in the context of radiation.

Publications:
Gastrointestinal acute radiation syndrome: current knowledge and perspectives.
Freeman ML.
Cell Death Discov. 2025 May 14;11(1):235

Nucleophosmin Plays a Role in Repairing DNA Damage and Is a Target for Cancer Treatment.
Sekhar KR, Freeman ML.
Cancer Res. 2023

Targeting NPM1 in irradiated cells inhibits NPM1 binding to RAD51, RAD51 foci formation and radiosensitizes NSCLC.
Traver G, Sekhar KR, Crooks PA, Keeney DS, Freeman ML.
Cancer Lett. 2021 Mar 1;500:220-227

Grants:
NIH/NCI The Thromboxane-Prostanoid Receptor in Radiation-Induced Pulmonary
Fibrosis Multi-PIs James West and Michael L Freeman.

BARDA/Draper Human Tissue Models of Radiation-Induced Damage to Enable Medical
Countermeasure Discovery”. Animal models PI Michael L Freeman

NOAA Improving Emergency Communications and Preparedness
among the Deaf and Hard of Hearing Community. Multi PI: C Wang, JJ Walsh, and ML Freeman,