Poster Presentation 36th Lorne Cancer Conference 2024

Elucidating causative mechanisms of late effects using a clinically relevant model of radiotherapy in the developing mouse brain (#138)

Aiden Boonnark 1 2 , Jacqueline Whitehouse 1 2 , Meegan Howlett 1 2 , Annabel Short 1 2 , Jessica Buck 1 2 , Kale Somers 2 , Jessica Lawler 2 , Chelsea Rowley 3 , Hilary Hii 1 , Brooke Carline 1 , Mani Kuchibhotla 1 , Bhedita J Sewoo 2 4 , Tim Rosenow 2 , Kirk Feindel 2 , Martin A Ebert 2 5 , Andrew JH Mehnert 2 6 , Nicholas G Gottardo 1 7 , Raelene Endersby 1 2
  1. Telethon Kids Institute, Perth, WA, Australia
  2. The University of Western Australia, Perth, Western Australia, Australia
  3. University of Sydney, Sydney, New South Wales, Australia
  4. Perron Institute for Neurological and Translational Science, Perth, WA, Australia
  5. Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
  6. Lions Eye Institute, Perth, Western Australia, Australia
  7. Perth Children's Hospital, Perth, Western Australia, Australia

Background: Children with brain cancer treated with radiotherapy commonly develop detrimental long-term side effects (late effects) including hormonal deficiencies, growth defects and neurocognitive impairment. Preclinical models allow researchers to test new therapies, whilst examining their impact on late effects. However, past studies have utilised a single high-dose of radiation which does not mimic fractionated schedules used in the clinic. Objective: This project aimed to examine and compare long-term neurostructural and cellular changes following a single high-dose of radiotherapy compared with fractionated radiotherapy in mice. Method: Juvenile mice were treated at postnatal day 16 with a single dose (8 Gy) whole brain irradiation, or a clinically relevant, mathematically-equivalent fractionated dose (18 Gy, 9 x 2 Gy daily fractions). Sham control mice received cone-beam computed tomography (CBCT) scans, or 9 x CBCT scans. At adulthood (post-natal day 63), ex vivo anatomical magnetic resonance imaging (MRI) scans were performed along with histology, with sex-specific differences examined. Results: Whole brain irradiation resulted in widespread region-specific volume deficits. A single high-dose of radiation resulted in greater volume reductions compared to a fractionated schedule. No sex-specific differences were detected as a result of cranial irradiation. Neural-lineage progenitor cells were depleted by cranial irradiation, and this was greater following a single high-dose of radiation. The number of microglia in the hippocampus were significantly reduced by cranial irradiation. Granule neuron density was not significantly impacted by radiation in volume-affected brain regions. Conclusions: A single high-dose of radiation does not produce the same biological outcomes as multifractionated radiation in the developing mouse brain. In radiosensitive neurogenic regions, volume loss may be an indirect result of depleted neural-lineage progenitor cells. Radiation-induced volume deficits are unlikely the result of a reduction in neuron density. For future preclinical late effect research, fractionated radiation should be utilised to accurately model late effects seen in childhood survivors of brain cancer to ensure children with brain cancer receive both effective and safe treatments, giving them the best chance to live longer, healthier lives.