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Figure SF3 from FLASH Proton Radiotherapy Spares Normal Epithelial and Mesenchymal Tissues While Preserving Sarcoma Response

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posted on 2023-03-30, 14:20 authored by Anastasia Velalopoulou, Ilias V. Karagounis, Gwendolyn M. Cramer, Michele M. Kim, Giorgos Skoufos, Denisa Goia, Sarah Hagan, Ioannis I. Verginadis, Khayrullo Shoniyozov, June Chiango, Michelle Cerullo, Kelley Varner, Lutian Yao, Ling Qin, Artemis G. Hatzigeorgiou, Andy J. Minn, Mary Putt, Matthew Lanza, Charles-Antoine Assenmacher, Enrico Radaelli, Jennifer Huck, Eric Diffenderfer, Lei Dong, James Metz, Constantinos Koumenis, Keith A. Cengel, Amit Maity, Theresa M. Busch

Figure S3 F-PRT-treated mouse skin experiences less hair follicle atrophy than S-PRT-treated skin. TUNEL assay depicts apoptosis in the hair follicles at 5 days after S-PRT. Red identifies apoptotic cells and blue Hoechst-stained nuclei. Scale bar, 50Î1/4m.

Funding

Department of Radiation Oncology, University of Pennsylvania

Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania

Greece and European Social Fund-ESF

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ARTICLE ABSTRACT

In studies of electron and proton radiotherapy, ultrahigh dose rates of FLASH radiotherapy appear to produce fewer toxicities than standard dose rates while maintaining local tumor control. FLASH-proton radiotherapy (F-PRT) brings the spatial advantages of PRT to FLASH dose rates (>40 Gy/second), making it important to understand if and how F-PRT spares normal tissues while providing antitumor efficacy that is equivalent to standard-proton radiotherapy (S-PRT). Here we studied PRT damage to skin and mesenchymal tissues of muscle and bone and found that F-PRT of the C57BL/6 murine hind leg produced fewer severe toxicities leading to death or requiring euthanasia than S-PRT of the same dose. RNA-seq analyses of murine skin and bone revealed pathways upregulated by S-PRT yet unaltered by F-PRT, such as apoptosis signaling and keratinocyte differentiation in skin, as well as osteoclast differentiation and chondrocyte development in bone. Corroborating these findings, F-PRT reduced skin injury, stem cell depletion, and inflammation, mitigated late effects including lymphedema, and decreased histopathologically detected myofiber atrophy, bone resorption, hair follicle atrophy, and epidermal hyperplasia. F-PRT was equipotent to S-PRT in control of two murine sarcoma models, including at an orthotopic intramuscular site, thereby establishing its relevance to mesenchymal cancers. Finally, S-PRT produced greater increases in TGFβ1 in murine skin and the skin of canines enrolled in a phase I study of F-PRT versus S-PRT. Collectively, these data provide novel insights into F-PRT-mediated tissue sparing and support its ongoing investigation in applications that would benefit from this sparing of skin and mesenchymal tissues. These findings will spur investigation of FLASH radiotherapy in sarcoma and additional cancers where mesenchymal tissues are at risk, including head and neck cancer, breast cancer, and pelvic malignancies.

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