(MRC DTP) Mitigating radiotherapy-induced neuroinflammation and toxicity through inhibition of DNA-damage repair pathway components: biological mechanisms and therapeutic potential

A common component of many neurological conditions is neuroinflammation. Studies have suggested a causal link between neuroinflammation and neurodegeneration in multiple diseases including Alzheimer’s, Parkinson’s and multiple sclerosis. Neuroinflammation occurs post-stroke and is also observed as one of the sequela of events elicited post-irradiation of brain tissue during cancer treatment. In brain and head and neck cancers, radiotherapy (RT) is used with curative intent. However, during treatment, significant volumes of normal brain are also irradiated. Consequently whilst RT extends patient survival, it can also lead to irreversible, progressive deterioration in cognitive function with devastating effects on quality-of-life. Multiple processes have been associated with RT-induced neurotoxicity. However specific mediators and temporal relationships between biological responses remain unclear. Poly(ADP-ribose) polymerase (PARP) is a key component of the DNA damage response (DDR) and a validated target for anti-cancer therapy. Recent data in stroke and brain trauma suggest that PARP activation is detrimental post-injury. Indeed in experimental models of stroke, PARP inhibition can have positive impact on outcome. The possibility arises that PARP inhibition may mitigate adverse RT effects on the normal brain. This PhD proposal aims to investigate biological responses following brain RT using rodent models and evaluate the potential of clinically relevant PARP inhibitors to ameliorate neurotoxicity. The project has three work-packages, aiming to 1) Define the temporal relationship between PARP activation, neuroinflammation and downstream cellular and tissue events associated with RT-induced neurotoxicity; 2) Evaluate the potential of PARP inhibitors to mitigate neuroinflammation and downstream pathology; 3) Translate mitigation of neuroinflammation/neurodegeneration to therapeutic benefit by evaluating impact on cognitive impairment through behavioural studies. Initial work will build on pilot data evaluating brain neuroinflammation over time using state-of-the-art non-invasive positron emission tomography (PET)-based imaging of the neuroinflammatory marker [18F-DPA714]. Preliminary studies revealed elevated [18F-DPA714] post-brain RT. These data will be confirmed with cross-validation of [18F-DPA714] uptake with tissue analyses evaluating cellular and biological changes associated with neuroinflammation and neurodegeneration. The protective effect of PARP-inhibition will be evaluated by investigating whether PARP inhibition changes the cellular response observed in irradiated brain tissue suggestive of neuroprotection. Rescue of phenotype will then be translated in to a clinical relevant outcome measure by assessing the impact of PARP-inhibition on subtle behaviours that are indicative of cognitive function. The key translational relevance is that PARP inhibitors have the potential to both protect normal tissue whilst enhancing tumour response: a step change in any RT molecular-targeted therapy combination.
https://www.research.manchester.ac.uk/portal/Kaye.Williams.html
https://www.research.manchester.ac.uk/portal/michael.harte.html
https://www.research.manchester.ac.uk/portal/Herve.Boutin.html