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Thu, 01.01.1970
MECHANISMS OF FLASH RADIOTHERAPY SPARING OF NORMAL TISSUE AS INFORMED BY RNA-SEQ TRANSCRIPTOME ANALYSES
Abstract
Background and Aims
The ultra-high dose rates of FLASH radiotherapy can reduce the severity of both acute damage and chronic side effects from radiation of normal tissues. For many disease sites, treatment with radiotherapy puts the skin at risk of toxicities that compromise its barrier and protective functions. Using RNAseq, we investigated the effects of FLASH versus standard proton radiotherapy on skin, identifying transcriptome-level differentials in response that inform mechanisms by which FLASH may spare normal tissues from radiotherapy-induced toxicities.
Methods
Clinical and histological responses of C57BL/6 mice to FLASH and standard proton radiotherapy were assessed for respective dose rates of 69-124 Gy/sec and 0.39-0.65 Gy/sec. RNAseq was performed of full thickness skin, collected at 5 days after irradiation. All studies irradiated the mouse hind limb to a total dose of 30 Gy.
Results
FLASH proton radiotherapy (F-PRT) significantly spared murine skin relative to standard proton radiotherapy (S-PRT), with corroborating pathological findings that F-PRT produced less epidermal necrosis than S-PRT. From RNAseq data, pathways upregulated by S-PRT included those involved in apoptosis and keratin signaling. In contrast, F-PRT increased signaling in pathways related to tissue and vascular repair, such as blood vessel morphogenesis and vascular development. Genes that were differentially uprelated after F-PRT included platelet/endothelial cell adhesion molecule and family members of the matrix metalloproteinases and fibroblast growth factors that associate with wound healing.
Conclusions
RNAseq analyses offer insight in mechanisms of F-PRT sparing that include greater induction of tissue damage by S-PDT and more upregulation of repair by F-PRT.