David G. Kirsch (United States of America)
Duke University Medical Center Radiation OncologyAuthor Of 1 Presentation
PRECLINICAL STUDIES WITH PROTON FLASH RADIOTHERAPY: BIOLOGICAL EFFECTS AND POTENTIAL MECHANISMS.
Abstract
Background and Aims
Our group has designed and tested the first system to accurately deliver dosimetrically identical FLASH Proton RT (F-PRT; 60-110 Gy/sec) or Standard Proton RT (S-PRT; 0.5-1 Gy/sec) using double-scattered protons. Our purpose is to identify if F-PRT is superior to S-PRT in protecting normal tissues, while equipotent in controlling tumor growth.
Methods
Masson’s trichrome staining, EdU pulsing and single-cell RNA sequencing (scRNA-seq), were used in this study.
Results
We found that F-PRT preserved a significantly higher percentage of regenerated crypts (p<0.01; EdU pulsing) accompanied by a significant increase in overall survival (p<0.01) compared to the S-PRT following 15Gy of whole-abdomen radiation. Moreover, trichrome staining revealed significantly reduced levels of fibrosis (p<0.001) in the F-PRT treated intestines compared to the high levels observed in the S-PRT group. scRNA-seq on 15Gy F-PRT and S-PRT treated intestines, revealed enrichment of stem/progenitor epithelial cell populations with increased proliferative signatures and expression of genes related to the interferon-alpha signature in epithelial and immune cells post F-PRT treatment compared to the S-PRT. Finally, F-PRT was equipotent with S-PRT in controlling syngeneic pancreatic tumor growth in the same mouse strain.
Conclusions
Our preliminary findings suggest that F-PRT may enhance a regenerative, or facultative stem cell program that is associated with greater and more persistent IFN Type I signaling. Understanding the cellular and molecular basis for the effects of F-PRT provides a framework for clinical application of this novel modality with the potential to improve the therapeutic outcome and quality of life of cancer patients.