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Kris Sarosiek (Harvard T.H. Chan School of Medicine), Developmental regulation of apoptosis as a modifiable driver of radiotherapy-induced neurocognitive impairment in pediatric patients
Tuesday 06 August 2019, 12:00pm - 01:00pm

Pediatric cancer patients treated with external beam radiation therapy (xRT) or cytotoxic chemotherapy have a high risk of developing long-term toxicities including neurocognitive dysfunction and chronic heart failure, limiting the use of potentially curative therapies. These treatments, which rely on the preferential induction of an apoptotic cell death in cancer cells over healthy tissues, are better tolerated in adults, yet the molecular basis for this difference in sensitivity was previously unknown. We have previously reported that apoptosis is dynamically regulated during postnatal development in healthy tissues, altering cell fate in response to genotoxic damage induced by anti-cancer therapies. Specifically, we found that many somatic tissues, including the brain, heart, kidneys and skeletal muscle, are highly primed for apoptosis in very young mice and humans but become apoptosis resistant by late childhood and remain in that state throughout adult life. These phenotypes are linked to developmental and proliferative states that regulate apoptosis via Myc-driven modulation of BCL-2 family protein expression including BAX. We have recently developed multiple mouse models of treatment-induced toxicities to test the role of apoptosis regulation in relevant clinical outcomes including neuro- and cardio-toxicity. We found that xRT-induced, BAX-dependent apoptosis in neural stem and progenitor cells impairs neurogenesis and gliogenesis across multiple regions of the developing brain. This results in dose- and age-dependent neurocognitive and motor impairments that mirror those commonly observed post xRT in pediatric brain tumor patients. Genetic loss of BAX protects neural stem and progenitor cells from radiation-induced apoptosis and prevents thinning of critical brain regions including the dentate gyrus and subventricular zone. Importantly, BAX loss also rescues xRT-induced neurocognitive impairment and enables proficient DNA repair in surviving cells. Our studies identify xRT-induced apoptosis of neural stem cells as a major driver of neurocognitive impairment in pediatric brain cancer patients and demonstrate the potential for reversing neurotoxicity by modulating apoptosis, which may be possible with novel treatment strategies that we are validating.

Location : Goitein Room