ESTRO 2024 - Abstract Book

S5359

Radiobiology - Tumour biology

ESTRO 2024

Keywords: Spheroids, Hypoxia, OXPHOS inhibitors

989

Digital Poster

The radiobiology of protons in head and neck cancer models: Influence of LET, hypoxia and FLASH

Maria Fabbrizi, Jonathan Hughes, Chun Li, Elizabeth Dufficy, Jason Parsons

University of Birmingham, Institute of Cancer and Genomic Sciences, Birmingham, United Kingdom

Purpose/Objective:

Proton beam therapy (PBT) is increasingly being utilised for the treatment of solid tumours, including head and neck squamous cell carcinoma (HNSCC). However, biological and clinical uncertainty exists due to the increases in linear energy transfer (LET) at and around the Bragg peak where the majority of the radiation dose is deposited, leading to changes in DNA damage complexity (containing multiple DNA lesions in one or two helical turns of the DNA) and relative biological effectiveness 1 . Hypoxia is a well known factor driving radioresistance in solid tumours such as HNSCC 2 , and the significant interest in utilising radiotherapy at ultra-high dose rates (FLASH) 3 are other important biological and physical factors that require further exploration in relation to PBT.

Material/Methods:

We are currently utilising the 40 MeV cyclotron at the University of Birmingham to examine the impact of PBT of increasing LET at and around the Bragg peak on cell models of HNSCC through monitoring clonogenic cell survival and the levels and repair of DNA single and double strand breaks plus complex DNA damage (e.g. comet assays and γH2AX/53BP1 foci). Protein targets for radiosensitisation at both low- and high-LET has been explored through siRNA screening as well as using a targeted drug approach. We have also begun exploring the impact of mild hypoxia (1 % oxygen) on PBT radiobiology, as well as examining PBT delivered at conventional versus FLASH dose rates (60 Gy/s) to investigate the cellular response mechanisms involved.

Results:

We have previously demonstrated that PBT of increasing LET leads to reduced survival of HNSCC cells proportional to the levels of complex DNA damage 4 . We have also identified specific cellular proteins within the cellular DNA damage response that when targeted with inhibitors can enhance the radiosensitivity of HNSCC cells and 3D spheroids to low-LET PBT (particularly ataxia telangiectasia mutated, ATM; and DNA-dependent protein kinase, DNA PK) and specifically relatively high-LET PBT (8-oxoguanine DNA glycosylase, OGG1; poly(ADP-ribose) polymerase, PARP; and poly(ADP-ribose) glycohydrolase, PARG) 5,6 . We have begun to explore HNSCC cells grown and irradiated in mild hypoxia that demonstrate enhanced radioresistance to X-rays, and to identify the mechanisms coordinating this effect. Our preliminary evidence also reveals that PBT of increased LET can at least partly overcome hypoxia-induced radioresistance. Finally, we have shown that low-LET PBT delivered at FLASH dose rates (60 Gy/s) can produce cell