Identifying pathogenic contributors of radiodermatitis ameliorated by Smad7-based targeting in canine and mouse models

Yao Ke; Mary-Keara Boss; Braden Burdekin; Ben-Zheng Li; Li Bian; Donna Wang; Suyan Wang; Ber-In Lee; Patricia Gualtieri; Erin Trageser; Christian D Young; Xiao-Jing Wang

doi:10.1016/j.ijrobp.2025.05.082

Identifying pathogenic contributors of radiodermatitis ameliorated by Smad7-based targeting in canine and mouse models

Int J Radiat Oncol Biol Phys. 2025 Jun 16:S0360-3016(25)03902-1. doi: 10.1016/j.ijrobp.2025.05.082. Online ahead of print.

Authors

Yao Ke¹, Mary-Keara Boss², Braden Burdekin³, Ben-Zheng Li⁴, Li Bian⁵, Donna Wang⁶, Suyan Wang⁶, Ber-In Lee³, Patricia Gualtieri³, Erin Trageser³, Christian D Young⁷, Xiao-Jing Wang⁸

Affiliations

¹ Department of Pathology & Laboratory Medicine, University of California Davis Medical Center, Sacramento, CA; Department of Pathology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO.
² Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO. Electronic address: Keara.Boss@colostate.edu.
³ Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO.
⁴ Department of Physiology and Biophysics, University of Colorado, Anschutz Medical Campus, Aurora, CO.
⁵ Department of Pathology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO.
⁶ Allander Biotechnologies, Aurora, CO.
⁷ Department of Pathology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO; Allander Biotechnologies, Aurora, CO. Electronic address: Christian.Young@allanderbiotech.com.
⁸ Department of Pathology & Laboratory Medicine, University of California Davis Medical Center, Sacramento, CA; Department of Pathology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO; Allander Biotechnologies, Aurora, CO. Electronic address: drxwang@ucdavis.edu.

PMID: 40532891
DOI: 10.1016/j.ijrobp.2025.05.082

Abstract

Purpose: Acute radiodermatitis is a significant complication of radiotherapy (RT) treatment without effective therapy. This study aims to establish a canine radiodermatitis model and explore a therapeutic intervention to treat radiodermatitis.

Methods: AND.

Materials: We developed a canine radiodermatitis model using hypofractionated RT regimens and evaluated the therapeutic potential of topical Tat-PYC-Smad7, a Smad7-based biologic targeting TGFβ and NFκB signaling pathways. Skin biopsies were collected before RT, after radiodermatitis onset, and post-treatment for histopathology, immunostaining, and RNA sequencing (RNAseq). ELISA assessed systemic absorption and anti-drug antibody (ADA) responses. We also examined radiodermatitis in K5.Smad7 transgenic mice, which overexpress Smad7 in the epidermis. WT and K5.Smad7 mice underwent skin irradiation; radiation-induced dermatitis was monitored and analyzed by histopathology and immunostaining.

Results: Hypofractionated RT using doses of 25-40Gy in 5 fractions with 6 MV X-ray IMRT or 42-48Gy in 10 fractions with 50 kV superficial X-ray system induced radiodermatitis in dogs within two weeks post-RT. Tat-PYC-Smad7 treatment significantly reduced radiodermatitis severity, effectively penetrating keratinocytes and stromal cells without systemic absorption or ADA formation. RNAseq and immunostaining showed reduced DNA damage, neutrophil infiltration, and fibrotic response in treated lesions with inhibited TGFβ, NFκB, and JAK/STAT3 signaling. Consistently, K5.Smad7 mice exhibited accelerated radiodermatitis recovery with reduced inflammation and fibrotic response and improved DNA repair compared to WT mice.

Conclusion: Our study demonstrates that the newly developed radiodermatitis canine model is a valuable tool for studying molecular mechanisms and therapeutic interventions for radiodermatitis. Topical application of Tat-PYC-Smad7 mitigates radiodermatitis by targeting critical pathogenic pathways while minimizing systemic side effects. Similar findings in K5.Smad7 mice suggested that Tat-PYC-Smad7 therapeutic effects largely represent functions of Smad7 protein.

Keywords: healing; inflammation; side effect.