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ResearchIn-Press PreviewOncology Open Access | 10.1172/JCI173649

TRAIL agonists rescue mice from radiation-induced lung, skin or esophageal injury

Jillian Strandberg,1 Anna Louie,1 Seulki Lee,2 Marina Hahn,1 Praveen Srinivasan,1 Andrew George,1 Arielle De La Cruz,1 Leiqing Zhang,1 Liz Hernandez Borrero,1 Kelsey E. Huntington,1 Payton De La Cruz,3 Attila A. Seyhan,1 Paul P. Koffer,3 David E. Wazer,3 Thomas A. DiPetrillo,3 Stephanie L. Graff,3 Christopher G. Azzoli,3 Sharon I. Rounds,3 Andres J. Klein-Szanto,4 Fabio Tavora,5 Evgeny Yakirevich,3 Abbas E. Abbas,3 Lanlan Zhou,1 and Wafik S. El-Deiry1

1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

Find articles by Strandberg, J. in: JCI | PubMed | Google Scholar

1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

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1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

Find articles by Lee, S. in: JCI | PubMed | Google Scholar

1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

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1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

Find articles by Srinivasan, P. in: JCI | PubMed | Google Scholar

1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

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1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

Find articles by De La Cruz, A. in: JCI | PubMed | Google Scholar

1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

Find articles by Zhang, L. in: JCI | PubMed | Google Scholar

1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

Find articles by Hernandez Borrero, L. in: JCI | PubMed | Google Scholar

1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

Find articles by Huntington, K. in: JCI | PubMed | Google Scholar |

1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

Find articles by De La Cruz, P. in: JCI | PubMed | Google Scholar

1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

Find articles by Seyhan, A. in: JCI | PubMed | Google Scholar |

1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

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1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

Find articles by Wazer, D. in: JCI | PubMed | Google Scholar

1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

Find articles by DiPetrillo, T. in: JCI | PubMed | Google Scholar

1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

Find articles by Graff, S. in: JCI | PubMed | Google Scholar

1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

Find articles by Azzoli, C. in: JCI | PubMed | Google Scholar

1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

Find articles by Rounds, S. in: JCI | PubMed | Google Scholar

1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

Find articles by Klein-Szanto, A. in: JCI | PubMed | Google Scholar |

1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

Find articles by Tavora, F. in: JCI | PubMed | Google Scholar

1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

Find articles by Yakirevich, E. in: JCI | PubMed | Google Scholar

1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

Find articles by Abbas, A. in: JCI | PubMed | Google Scholar

1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

Find articles by Zhou, L. in: JCI | PubMed | Google Scholar

1Laboratory of Translational Oncology and Translational Cancer Therapeutics, Warren Alpert Medical School of Brown University, Providence, United States of America

2D&D Pharmatech, Gaithersburg, United States of America

3The Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, United States of America

4Fox Chase Cancer Center, Philadelphia, United States of America

5Argos Laboratory, Universidade Federal do Ceará Fortaleza, Ceará, Brazil

Find articles by El-Deiry, W. in: JCI | PubMed | Google Scholar |

Published January 14, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI173649.
Copyright © 2025, Strandberg et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 14, 2025 - Version history
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Abstract

Radiotherapy can be limited by pneumonitis which is impacted by innate immunity, including pathways regulated by TRAIL death receptor DR5. We investigated whether DR5 agonists could rescue mice from toxic effects of radiation and found two different agonists, parenteral PEGylated trimeric-TRAIL (TLY012) and oral TRAIL-Inducing Compound (TIC10/ONC201) could reduce pneumonitis, alveolar-wall thickness, and oxygen desaturation. Lung protection extended to late effects of radiation including less fibrosis at 22-weeks in TLY012-rescued survivors versus un-rescued surviving irradiated-mice. Wild-type orthotopic breast tumor-bearing mice receiving 20-Gy thoracic radiation were protected from pneumonitis with disappearance of tumors. At the molecular level, radioprotection appeared due to inhibition of CCL22, a macrophage-derived chemokine previously associated with radiation pneumonitis and pulmonary fibrosis. Treatment with anti-CCL22 reduced lung injury in vivo but less so than TLY012. Pneumonitis severity was worse in female versus male mice, and this was associated with increased expression of X-linked TLR7. Irradiated mice had reduced esophagitis characterized by reduced epithelial disruption and muscularis externa thickness following treatment with ONC201 analogue ONC212. The discovery that short-term treatment with TRAIL pathway agonists effectively rescues animals from pneumonitis, dermatitis and esophagitis following high doses of thoracic radiation exposure has important translational implications.

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  • Version 1 (January 14, 2025): In-Press Preview
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