Investigating the mechanistic basis of photon FLASH radiotherapy in tumours & normal tissues
Lead Research Organisation:
Queen's University Belfast
Department Name: Sch of Medicine, Dentistry & Biomed Sci
Abstract
Radiotherapy is an excellent treatment for many types of cancer and about half of all patients can be cured by its use. A new approach involves the delivery of radiotherapy at ultra-high dose rates, known as FLASH radiotherapy. This innovative approach can reduce the unwanted side effects of radiotherapy whilst maintaining its cell-killing effects in tumours. Currently, the vast majority of FLASH studies have been performed using types of radiotherapy (protons and electrons) that are not used in most clinical treatments delivered that use photons.
Recent MRC funding to our laboratory has allowed as to establish one of the world's first photon FLASH radiotherapy research facilities. This leading-edge technology enables new lines of research into the effects of radiotherapy at ultra-high dose rates using a radiation source that is much closer to the majority of clinical treatments.
In this project, we will use this state-of-the-art technology to explore how normal tissues and tumours respond to FLASH radiotherapy. Using different experimental methods, we will gain a better understanding of how FLASH-RT works and use this knowledge to further optimize treatments. This work will lead to improved models that will facilitate the development of FLASH-RT towards the clinic ultimately aiming to improve outcomes for patients receiving radiotherapy.
Recent MRC funding to our laboratory has allowed as to establish one of the world's first photon FLASH radiotherapy research facilities. This leading-edge technology enables new lines of research into the effects of radiotherapy at ultra-high dose rates using a radiation source that is much closer to the majority of clinical treatments.
In this project, we will use this state-of-the-art technology to explore how normal tissues and tumours respond to FLASH radiotherapy. Using different experimental methods, we will gain a better understanding of how FLASH-RT works and use this knowledge to further optimize treatments. This work will lead to improved models that will facilitate the development of FLASH-RT towards the clinic ultimately aiming to improve outcomes for patients receiving radiotherapy.
Technical Summary
The delivery of radiation at higher dose rates than used conventionally has been shown to preferentially spare normal tissue while preserving efficacy in tumour control - the 'FLASH' effect. This has the potential to revolutionise radiotherapy, significantly improving patient outcomes, but must be robustly characterised before it can be translated to the clinic.
A challenge is that most data on FLASH effects has been gathered using electrons and protons, while the majority of both experimental and clinical radiobiology uses photons. This slows translation, preventing direct benchmarking of observations against published data.
We have received funding to acquire a FLASH-SARRP, which is the first preclinical platform which can deliver radiation at FLASH rates, with onboard CT imaging to enable precision studies in animal models. We propose to use this platform to deliver a first-of-its kind systematic characterization of photon FLASH radiobiology, leveraging our extensive expertise in animal models to quantify FLASH effects in a range of normal tissues and tumours.
We will characterize normal tissue dose and dose-rate effects in lung (using our established models of pneumonitis and fibrosis), skin, gut, and the immune system. We will compare toxicity as a function of dose-rate to identify thresholds and magnitudes of FLASH sparing, and collect samples for subsequent molecular analysis. In tumours, we will also characterise dose and dose-rate effects to verify that efficacy is not reduced. We will probe the impacts of tumour biology and microenvironment by regulating oxygen levels, and using subcutaneous, orthotopic and endogenous tumour models. Finally, we will analyse genetic, metabolic, immunological and radiomic changes in different tissues when exposed to conventional and FLASH radiotherapy to begin to map the underlying mechanisms of these effects.
This work will give a unique, systematic characterisation of photon-FLASH radiotherapy.
A challenge is that most data on FLASH effects has been gathered using electrons and protons, while the majority of both experimental and clinical radiobiology uses photons. This slows translation, preventing direct benchmarking of observations against published data.
We have received funding to acquire a FLASH-SARRP, which is the first preclinical platform which can deliver radiation at FLASH rates, with onboard CT imaging to enable precision studies in animal models. We propose to use this platform to deliver a first-of-its kind systematic characterization of photon FLASH radiobiology, leveraging our extensive expertise in animal models to quantify FLASH effects in a range of normal tissues and tumours.
We will characterize normal tissue dose and dose-rate effects in lung (using our established models of pneumonitis and fibrosis), skin, gut, and the immune system. We will compare toxicity as a function of dose-rate to identify thresholds and magnitudes of FLASH sparing, and collect samples for subsequent molecular analysis. In tumours, we will also characterise dose and dose-rate effects to verify that efficacy is not reduced. We will probe the impacts of tumour biology and microenvironment by regulating oxygen levels, and using subcutaneous, orthotopic and endogenous tumour models. Finally, we will analyse genetic, metabolic, immunological and radiomic changes in different tissues when exposed to conventional and FLASH radiotherapy to begin to map the underlying mechanisms of these effects.
This work will give a unique, systematic characterisation of photon-FLASH radiotherapy.
