Presenter 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.
Author Of 2 Presentations
FLASH PROTON RADIOTHERAPY IS EQUIPOTENT TO STANDARD RADIATION IN TREATMENT OF MURINE SARCOMAS WHILE REDUCING TOXICITIES TO NORMAL SKIN, MUSCLE AND BONE
Abstract
Background and Aims
Compared to Standard dose rates, the high dose rates of FLASH radiation can reduce radiotherapy toxicities to normal tissues. We examined the potential of FLASH-proton radiotherapy (F-PRT) to treat murine sarcomas and protect normal epithelial and mesenchymal tissues relative to the effects of standard-proton radiotherapy (S-PRT).
Methods
Mice received 30 or 45 Gy of F-PRT (69-124 Gy/sec) or S-PRT (0.39–0.65 Gy/sec) to their hind legs. Skin, muscle and bone injuries were recorded as acute through chronic macroscopic and/or microscopic observations of radiation-induced damage. Murine skin and bone RNAseq analyses were performed to delineate involved mechanisms. Skin stem cell depletion, inflammatory reaction and TGF-β levels were evaluated, and antitumor efficacy of F-PRT was compared to S-PRT in two murine models of sarcoma.
Results
Fewer severe morbidities were induced by F-PRT, with RNAseq revealing S-PRT to upregulate pathways involved in apoptosis signaling and keratinocyte differentiation in skin, and osteoclast differentiation and chondrocyte development in bone. Accordingly, F-PRT reduced skin injury, stem cell depletion and inflammation; mitigated lymphedema; and decreased myofiber atrophy, bone resorption, hair follicle atrophy, and epidermal hyperplasia. Equipotent control of sarcoma growth was achieved by the radiation modalities. Finally, S-PRT produced higher levels of TGF-β1 in murine skin than did F-PRT, and this finding was corroborated in the skin samples of dogs treated on a F-PRT clinical trial.
Conclusions
F-PRT can alleviate radiation-induced damage to both epithelial and mesenchymal tissues without compromise to sarcoma response; continuing investigation will further F-PRT translation to the clinic.
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.