ESTRO 2024 - Abstract Book

S5255 ESTRO 2024 Cranial irradiation frequently used in brain tumours. The effectiveness of brain irradiation is offset by irradiation of healthy brain tissue. This can lead to deficiencies in memory, attention and executive function, [1-3]. Neuroinflammation is thought to play a critical role in the pathology leading to downstream cognitive impairment [4-6]. [18F]-DPA-714 is a TSPO tracer that has been used to track neuroinflammation following cerebral ischaemia [7]. We used DPA-714 to track inflammatory changes post-radiotherapy, along with novel object recognition testing to elucidate the effects of irradiation on recognition memory. We demonstrate that Inhibition of poly (ADP-ribose) polymerase (PARP) by olaparib and pamiparib reduces radiation-induced neurotoxicity by reducing the neuroinflammatory response to radiation, reducing the severity of neurocognitive decline[AC1] . Radiobiology - Normal tissue radiobiology

[AC1]We haven’t shown the microglial effect for PARPi. And the NFkB mechanism is speculative at present. Suggest leaving this out.

Material/Methods:

Mice were given divided into four groups prior to irradiation.

Group 1 – Control; Group 2 – Radiation (RT) control; Group 3 – Olaparib; Group 4 – Pamiparib

Groups given PARPi therapy received the drug immediately prior to irradiation and for one week afterwards. Olaparib was dosed at 50mg/kg/day and pamiparib at 20mg/kg/day.

Following baseline testing, the right hemisphere of the brain was exposed to 20Gy image-guided irradiation under isoflurane anaesthesia using a small animal radiation research platform (SARRP, XSTRAHL, UK). Dynamic DPA-714 PET scans were performed at baseline, 1 week, 1 and 2 months post-irradiation using an Inveon PET-CT scanner (Siemens, Germany). Image analysis was performed using the BrainVisa/Anatomist framework (http://brainvisa.info/). Novel Object Recognition testing was undertaken at baseline, 1 week and 1-6 months post-RT. Novel object recognition measures the time taken investigating a novel object over a familiar one to arrive at a discrimination index (DI), calculated by DI = (time at novel object/time at familiar object). The data were analysed (in Graph Pad Prism using a repeated measures 2-way ANOVA with object exploration as the within-subjects factor and treatment as the between-subjects factor. In the retention trial, differences between the time spent at familiar and novel objects were assessed using planned* multiple comparison tests with Sidak's correction.

Ex vivo samples have been biobanked from the studies and are currently be analysed for histopathological integrity and markers of neuroinflammation, to correlate with imaging and behaviour metrics. .

Results:

Significantly increased DPA-714 uptake in terms of fold-change from baseline was observed in the subcortical region and the cortex and hippocampus at months 1 (p<0.01) and 2 (p<0.05) post-RT in the RT control group, when compared with control (sham-irradiated) animals (Fig.1). There was significantly lower DPA-714 uptake in these regions in the pamiparib group at 1 week (P<0.05) post-RT, and no significant differences were observed between the control group and the olaparib group in terms of DPA-714 uptake (Fig.1). These results indicate that increases in inflammation post-RT can be tracked longitudinally using DPA-714 PET scans in this model and that the increase in TSPO uptake observed 1 and 2 months following cranial irradiation is blunted by olaparib therapy. A decrease from baseline was observed following pamiparib therapy. The increased effect of pamiparib may be due to its superior brain penetrance compared to olaparib.