# Optimizing the therapeutic index for pediatric medulloblastomas by targeting apoptosis

> **NIH NIH F31** · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · 2021 · $34,886

## Abstract

Project Summary/Abstract
Medulloblastomas are the most prevalent malignant brain tumor affecting children, accounting for 20% of all
childhood brain tumors. Current therapies include surgical resection followed by postoperative radiotherapy
across the craniospinal axis, with an additional higher dose to the tumor bed. This treatment regimen, while
effective in eliminating medulloblastomas, also exposes healthy tissue to harmful levels of radiation, causing the
cells to undergo apoptosis, or programmed cell death. This loss of neural cells can lead to lifelong negative effects,
such as neurocognitive deficits and neuroendocrine dysfunction. Currently, clinicians must weigh the benefits of
radiation therapy against the permanent damage from these treatments, leading to a critical need for improved
therapies. As such, proton radiotherapy is being increasingly used clinically, as it reduces the entrance and exit
doses compared to more commonplace photon therapy while still allowing for adequate target coverage,
eliminating approximately half of the unnecessary radiation administered to normal tissue. Today,
approximately 50% of pediatric medulloblastoma patients in the United States receive post-surgery proton
radiation therapy. Even so, there is substantial healthy tissue being exposed to radiation, as medulloblastoma
patients receive radiation to the tumor bed as well as the entire craniospinal axis. Despite the clear importance
of maximizing post-treatment quality of life for pediatric cancer survivors, our understanding of the mechanisms
driving radiation induced neurotoxicity is limited, and no clinically-useful mitigators currently exist. Previous
studies have shown that genetic inhibition of BAX, a protein necessary for apoptosis, protects neural cells from
radiation induced apoptosis. While there are currently no well validated direct pharmacological BAX inhibitors,
Myc has been shown to directly promote the expression of BAX in the developing brain. Importantly, Myc also
has been shown to be a critical driver of medulloblastoma growth, and targeting this oncogene promotes stress-
induced apoptosis in medulloblastoma cells. Numerous inhibitors of Myc signaling have been developed,
including bromodomain and extra-terminal motif (BET) inhibitors that target the transcription of Myc itself, and
are currently being evaluated in clinical trials. These recent discoveries and developments create a potential
opportunity to modulate Myc to improve patient outcomes. We thus hypothesize that targeting Myc with BET
inhibitors will protect healthy neural cells from radiation induced apoptosis while simultaneously sensitizing
medulloblastomas to radiotherapy, thus widening the therapeutic window for radiotherapy. Our studies to date
show that BET inhibitors protect primary murine neurons from radiation induced apoptosis while potently
inducing apoptosis in medulloblastomas cells. As such, we propose to expand our studies to elucidate the optimal
manner in ...

## Key facts

- **NIH application ID:** 10316157
- **Project number:** 5F31CA246811-02
- **Recipient organization:** HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH
- **Principal Investigator:** Stacey Jessica Yu
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $34,886
- **Award type:** 5
- **Project period:** 2020-07-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10316157

## Citation

> US National Institutes of Health, RePORTER application 10316157, Optimizing the therapeutic index for pediatric medulloblastomas by targeting apoptosis (5F31CA246811-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10316157. Licensed CC0.

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