Developmental regulation of apoptosis as a modifiable driver of radiotherapy-induced neurocognitive impairment in pediatric patients

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ABSTRACT Central nervous system (CNS) tumors are a leading cause of cancer death and morbidity in children. CNS tumors, including the most common subtype – medulloblastomas, are routinely treated with external beam radiation therapy (xRT) as well as neurosurgery and chemotherapy, and improvements in these treatment modalities have increased survival and cure rates over the last four decades. However, over half of the pediatric patients treated with xRT experience life-altering neurocognitive impairment (NI), which is especially prominent in children diagnosed at a young age. In fact, young children commonly exhibit impairments in learning, memory, executive processing, visual acuity and fine motor coordination post xRT at vastly higher rates and with more severity than adults treated with similar doses. Despite the clear importance of maximizing post-treatment quality of life for childhood CNS cancer survivors, our understanding of the mechanisms driving xRT-induced neurotoxicity is limited and no clinically-useful mitigators currently exist. Apoptosis (programmed cell death) is an evolutionarily-conserved cell death pathway that is critical for normal development, maintenance of tissue homeostasis, and cancer prevention. This pathway is carefully controlled by the BCL-2 family of proteins, which contains both pro-apoptotic and pro-survival members that control the commitment to apoptotic cell death. Most anti-cancer therapies induce apoptosis in cancerous or normal cells by damaging key cellular components such as DNA or microtubules or by blocking key signaling pathways. We have found that apoptosis is dynamically regulated in healthy tissues during postnatal life. This regulation drives cell fate decisions in response to damage or stress and provides an explanation for why many children develop cognitive deficits from cancer treatments. In addition, we found that developing brain tissue can be protected from treatment-associated apoptosis by blocking BAX-mediated apoptosis. However, it is unclear which cells within the developing brain are most likely to undergo radiation-induced apoptosis at key developmental time points and how the loss of each cell type contributes to long-term neurocognitive sequelae. Within this proposal, we will 1) compare cell fates induced by xRT at the single cell level within neuronal, glial and vascular endothelial cells within the neonatal, juvenile and adult mouse brain and establish their role in xRT-induced NI and 2) evaluate the potential to reduce or eliminate xRT-induced neurotoxicity by blocking apoptosis genetically or pharmacologically (via upstream regulators) and the long-term effects of apoptosis inhibition. These studies will bring much-needed clarity to the field of xRT-induced neurotoxicity and lay the groundwork for future clinical applications that meaningfully improves the lives of pediatric brain cancer survivors and their families.