Document text
Principal Investigator: Kristopher Andrew Sarosiek
Organization: HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH
Fiscal Year: 2024
Award: $346,614
Funding agency: National Cancer Institute
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.
Terms: <0-11 years old><21+ years old><Adolescent><Adolescent Youth><Adult><Adult Human><Affect><After Care><After-Treatment><Aftercare><Age><Antioncogene Protein p53><Apoptosis><Apoptosis Pathway><Apoptotic><Astrocytes><Astrocytus><Astroglia><Automobile Driving><Autoregulation><B-Cell Chronic Lymphocytic Leukemia Associated Oncogene><B-cell Leukemia 1><BAX><BAX Isoform Alpha><BAX gene><BCL><BCL1 Oncogene><BCL2-Associated X Protein><BCL2-Associated X Protein Gene><BCL2L4><Bax protein><Biologic Models><Biological Models><Birth><Blood Vessels><Blood capillaries><Body Tissues><Brain><Brain Nervous System><Brain region><CNS Cancer><CNS Tumor><CNS neoplasm><Cancer Cause><Cancer Etiology><Cancer Survivor><Cancer Treatment><Cancerous><Caspase><Caspase Gene><Cell Body><Cell Communication and Signaling><Cell Cycle Arrest><Cell Death><Cell Signaling><Cell Survival><Cell Viability><Cell-Death Protease><Cells><Cellular Tumor Antigen P53><Cellular injury><Central Nervous System Cancer><Central Nervous System Neoplasms><Central Nervous System Tumors><Cephalic><Cessation of life><Chemotherapy and Radiation><Chemotherapy and/or radiation><Child><Child Youth><Childhood><Childhood CNS Neoplasm><Childhood CNS Tumor><Childhood Central Nervous System Neoplasm><Childhood Central Nervous System Tumor><Childhood Malignant Brain Tumor><Children (0-21)><Clinical><Cognitive deficits><Cranial><Cysteine Endopeptidases><Cysteine Protease><Cysteine Proteinases><DNA><DNA Damage Repair><DNA Repair><Death><Definitive Radiation Therapy><Dentate Fascia><Deoxyribonucleic Acid><Development><Diagnosis><Dose><EBRT><Encephalon><Exhibits><Exposure to><External Beam RT><External Beam Radiation Therapy><External Radiation><Family><Fascia Dentata><Female><Ferricytochrome c><Ferrocytochrome c><Future><Generalized Growth><Genetic><Goals><Growth><Gyrus Dentatus><Homeostasis><Human><ICE-like protease><IQ Deficit><Impairment><In Vitro><Induction of Apoptosis><Inhibition of Apoptosis><Intracellular Communication and Signaling><Knock-out><Knockout><Leanness><Learning><Life><Life Experience><Long-Term Effects><Longterm Effects><MYC Transcription Factor><Maintenance><Malignant CNS Neoplasms><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Tumor of the CNS><Malignant Tumor of the Central Nervous System><Malignant neoplasm of central nervous system><Measures><Mediating><Medulloblastoma><Memory><Mice><Mice Mammals><Micro-tubule><Microtubules><Modality><Model System><Modern Man><Morbidity><Morbidity - disease rate><Motor><Murine><Mus><Neonatal><Nerve Cells><Nerve Unit><Nervous System><Neural Cell><Neural Stem Cell><Neurocognitive><Neurocognitive Deficit><Neurocyte><Neurologic Body System><Neurologic Organ System><Neurons><Normal Cell><Oncogenesis><Oncoprotein p53><Outer Mitochondrial Membrane><P53><Parturition><Pathway interactions><Patients><Pediatric Malignant Brain Tumor><Permeability><Phenotype><Phosphoprotein P53><Phosphoprotein pp53><Physiological Homeostasis><Prevention><Progenitor Cells><Programmed Cell Death><Protein Family><Protein TP53><Proto-Oncogene Products c-myc><Proto-Oncogene Proteins c-myc><QOL><Quality of life><Radiation><Radiation therapy><Radiotherapeutics><Radiotherapy><Regulation><Reporting><Role><Severities><Shapes><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Stimulus><Stress><Synaptic plasticity><TP53><TP53 gene><TRP53><Testing><Thinness><Time><Tissue Growth><Tissues><Toxic effect><Toxicities><Tumor Protein p53><Tumor Protein p53 Gene><Unscheduled DNA Synthesis><VDAC1><VDAC1 gene><Vascular Endothelial Cell><Visual Acuity><adulthood><ages><anti-cancer therapy><astrocytic glia><biological signal transduction><brain tissue><c-myc Proteins><cancer cell><cancer of the central nervous system><cancer prevention><cancer therapy><cancer-directed therapy><capillary><cell damage><cell injury><cell type><cellular damage><chemo/radiation therapy><chemotherapy><chemotherapy and radiotherapy><child patients><childhood brain cancer><childhood cancer survivor><clinical applicability><clinical application><cognitive defects><conditional knock-out><conditional knockout><cystein protease><cystein proteinase><cysteine endopeptidase><cytochrome c><damage to cells><dentate gyrus><developmental><driving><external-beam radiation><improved><improved outcome><in vivo><injury to cells><innovate><innovation><innovative><intelligence quotient deficit><juvenile><juvenile human><kids><male><member><mouse model><murine model><myc Proto-Oncogene Product p62><myc Proto-Oncogene Proteins><necrocytosis><nerve stem cell><neural><neural precursor><neural precursor cell><neural progenitor><neural progenitor cells><neurocognitive decline><neurocognitive impairment><neurogenesis><neuron progenitors><neuron toxicity><neuronal><neuronal progenitor><neuronal progenitor cells><neuronal stem cells><neuronal toxicity><neuroprogenitor><neuroprotection><neuroprotective><neurosurgery><neurotoxicity><ontogeny><p53 Antigen><p53 Genes><p53 Tumor Suppressor><pathway><pediatric><pediatric CNS neoplasm><pediatric CNS tumor><pediatric brain cancer><pediatric cancer survivor><pediatric central nervous system neoplasm><pediatric central nervous system tumor><pediatric patients><pharmacologic><pore forming protein><porin><post treatment><postnatal><prevent><preventing><protein p53><radiation or chemotherapy><radiation treatment><response><senescence><senescent><social role><stem><stem cells><tool><treatment strategy><treatment with radiation><tumor><tumorigenesis><tumors in the central nervous system><vascular><youngster>