Moderator of 2 Sessions
Presenter of 1 Presentation
Biology of FLASH-RT in Vivo
Abstract
Abstract Body
FLASH radiotherapy (FLASH-RT) has come at the center of the attention in the radiobiology and radiation oncology fields. Taking into consideration the current literature, a possible definition for FLASH-RT could be: “A radiotherapy technique delivered at ultra-high dose rate with specific beam parameters able to treat tumors without inducing drastic toxicities on the surrounding normal tissues.” Nevertheless, there has been no consensus on a definition for FLASH-RT yet, and intensive work is currently ongoing to understand and decipher the mechanisms underlying the so-called “FLASH effect.”
The antitumor effect associated to an absence of normal tissue injury has caught the field by surprise, questioning the most basic concepts or radiobiology. But even if more and more studies describe a normal tissue protection following exposures to ultra-high dose rate irradiation, few biological mechanisms differentiating conventional dose rate RT to FLASH-RT responses have been described so far. This lecture aims at reviewing the most recent FLASH-RT literature to analyze the normal tissue and tumor response after FLASH RT at the molecular, cellular and tissular levels. A comprehensive approach of the different models and endpoints used in these studies will be provided to build up hypotheses on biological mechanisms explaining the FLASH effect.
Author Of 3 Presentations
Biology of FLASH-RT in Vivo
Abstract
Abstract Body
FLASH radiotherapy (FLASH-RT) has come at the center of the attention in the radiobiology and radiation oncology fields. Taking into consideration the current literature, a possible definition for FLASH-RT could be: “A radiotherapy technique delivered at ultra-high dose rate with specific beam parameters able to treat tumors without inducing drastic toxicities on the surrounding normal tissues.” Nevertheless, there has been no consensus on a definition for FLASH-RT yet, and intensive work is currently ongoing to understand and decipher the mechanisms underlying the so-called “FLASH effect.”
The antitumor effect associated to an absence of normal tissue injury has caught the field by surprise, questioning the most basic concepts or radiobiology. But even if more and more studies describe a normal tissue protection following exposures to ultra-high dose rate irradiation, few biological mechanisms differentiating conventional dose rate RT to FLASH-RT responses have been described so far. This lecture aims at reviewing the most recent FLASH-RT literature to analyze the normal tissue and tumor response after FLASH RT at the molecular, cellular and tissular levels. A comprehensive approach of the different models and endpoints used in these studies will be provided to build up hypotheses on biological mechanisms explaining the FLASH effect.
A PURSUIT FOR A HIGH-THROUGHPUT INDICATOR OF THE FLASH EFFECT
Abstract
Background and Aims
Despite an immense research interest in FLASH-RT, the precise beam requirements for obtaining the FLASH effect have still not been elucidated. Yet, there is an increasing number of reports assigning the name FLASH to beams and irradiators without any supportive biological data.Methods
Currently, the FLASH effect can be confirmed only in vivo, which requires time-consuming animal studies and corresponding ethical approvals. The FLASH community would therefore greatly benefit from a high-throughput FLASH beam indicator that can validate an UHDR beam for FLASH-RT. Such indicator has to generate an observable that follows the same dependency on temporal beam characteristics as the FLASH effect.Results
We used our published data on sparing of the normal mouse brain and killing of GBM to monitor the impact of gradually changing electron beam parameters (dose rate, dose per pulse) on the occurrence of the FLASH effect. These data were considered as a template to investigate responses of various high-throughput assays over the same range of beam parameters. In particular, we studied assays that previously showed differential response to our FLASH and Conv beams: H2O2 yield, O2 depletion, plasmid DSB, lipid peroxidation and zebrafish embryo. Only the length of zebrafishes grown from irradiated embryos showed the dependency on beam parameters mimicking the cognitive protection in vivo with low energy electron beam (Oriatron).Conclusions
Since mechanistic differences between different types of beams (protons, X-ray) are possible, further investigations are mandatory to confirm universal validity of this model as a general FLASH indicator.NOT JUST HEALTHY TISSUE SPARING: HYPOXIA DOES NOT IMPACT FLASH-RT ANTI-TUMOR EFFICACY
Abstract
Background and Aims
In this study, we investigated the effects of tumor oxygen tension on the anti-tumor efficacy of ultra-high-dose-rate (FLASH) radiotherapy (RT).
Methods
U87 glioblastoma cells were xenografted in Swiss Nude mice and irradiated using a single 20-Gy dose administered at UHDR (2 pulses, 100 Hz, 1.8 µs pulse width, 0.01 s delivery) or CONV (~ 0.1 Gy/s) dose rates with the Oriatron/eRT6 (PMB, CHUV) under normoxia, hypoxia (vascular clamp), and hyperoxia (carbogen breathing). In situ oxygen tension was measured during and following irradiation using an OxyLite probe. Tumor growth was monitored using caliper measurements and tumor were sampled for RNA and protein profiling (GIF, UNIL). Metabolic analysis and ROS measurements were performed in vitro using Seahorse XF96 Analyzer and CellROX.
Results
Surprisingly, the anti-tumor efficacy of FLASH-RT was not affected by hypoxia in this U87 xenograft model, whereas hypoxia induced radioresistance with CONV-RT. Genomic profiling revealed a decrease in hypoxia signaling in the FLASH-treated compared to the CONV-treated and control tumors 24h post-RT. Oxidative metabolism was also altered in response to FLASH-RT. Real-time tumor oxygen readout, ROS levels, and metabolic testing at different oxygen tensions and timepoints post-RT are in progress.
Conclusions
FLASH-RT anti-tumor efficacy does not seem to be affected by hypoxia supporting a differential role for oxygen signaling between FLASH and CONV-RT and opening new venues for clinical application of FLASH-RT in a subset of highly radiation resistant tumors.
Acknowledgement: The study is funded by SNF Synergia grant (FNS CRS II5_186369)