Reducing neurotoxicity from brain irradiation with FLASH radiation and PARP inhibitors

Background: The combination of PARPi and FLASH is of particular interest as both are shown to be modulated by the available oxygen in the irradiated tissue, which increases the possibility of a synergistic and beneficial effect when combining the two.

Radiation delivered at ultra-high dose rates has already been shown to result in similar treatment efficacy as radiation delivered at conventional radiotherapy dose rates, when evaluating tumour growth delay in a human glioblastoma model, subcutaneously implanted on the flank of nude mice or when using a murine orthotopic glioblastoma model similarly established in nude mice.

Whilst these studies emphasise the great clinical potential FLASH radiotherapy holds for the treatment of GBM as well as other brain tumours, enhanced normal tissue sparing via application of a PARPi will potentially lead to a further widening of the therapeutic window.

Aims: Using the state-of-art linear accelerator (Linac) we have available for pre-clinical studies at the University of Oxford, which is capable of delivering dose rates from conventional (few Gy/minute) to FLASH (thousands of Gy/s), we aim to investigate: 1) if hemi-brain FLASH radiation to 20 Gy induces a neuroinflammatory response and whether this is constrained to the radiation field 2) if acute PARP activation differs between conventional and FLASH RT 3) if FLASH- radiation in combination with PARPi can further spare normal brain tissue following hemibrain irradiation of mice These studies will be run in parallel to work to investigate whether PARPi can enhance the therapeutic impact of FLASH GBM models [funded outside of this application].

Methods: We will use IHC approaches to investigate temporal changes in oxidative stress [8-oxoguanine], DNA-damage response (γH2AX, 53BP1) and PARP activity (PARP-1, PAR) as a consequence of FLASH or conventional dose rate hemibrain irradiation.

We will complement IHC studies of brain pathology with non-invasive MRI and PET-CT studies monitoring neuroinflammatory responses, BBB function and neurodegeneration, following FLASH or conventional dose rate hemibrain irradiation of mice and the impact of PARPi thereupon. How the results of this research will be used: These will be the first studies combining FLASH and PARPi.

We will share technologies and expertise across the participating sites to support the progression of these studies. The results will be used for further and larger grant applications, e.g.

MRC or CRUK programme grants, further expanding the research collaboration between the universities in Oxford, Manchester and Glasgow.