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

> **NIH NIH R37** · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · 2022 · $364,856

## Abstract

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.

## Key facts

- **NIH application ID:** 10371055
- **Project number:** 5R37CA248565-03
- **Recipient organization:** HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH
- **Principal Investigator:** Kristopher Andrew Sarosiek
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $364,856
- **Award type:** 5
- **Project period:** 2020-03-09 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10371055

## Citation

> US National Institutes of Health, RePORTER application 10371055, Developmental regulation of apoptosis as a modifiable driver of radiotherapy-induced neurocognitive impairment in pediatric patients (5R37CA248565-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10371055. Licensed CC0.

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