# Y-Box 1 and normoxic HIF1 in Sonic hedgehog medulloblastoma tumor stem cell radiation resistance

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $341,500

## Abstract

Project Summary
Medulloblastomas are the most common malignant pediatric tumor of the central nervous system. The current
treatment paradigm for medulloblastomas includes surgical resection, irradiation of the tumor site and
craniospinal irradiation as well as chemotherapy. While this regimen is associated with a ~70% cure rate,
survivors are beset with long-term neurological side effects, and tumor recurrence is fatal. Thus, there is a need
to develop therapeutic approaches that reduce the requirement for irradiation, reduce the incidence of recurrence,
and may be successfully applied to patients that relapse. Medulloblastomas can be divided into 4 molecular
subgroups, one of which, the Sonic hedgehog (SHH) subgroup, is further divided into SHH with wild type p53 or
mutant p53, which bears the worst prognosis. The SHH subgroup features the most frequent local recurrence.
However, there is a limited understanding of mechanisms causing recurrence, and recent studies have shown
that genetic drivers of recurrence may be completely different than the original tumor drivers, rendering targeted
therapies against the primary tumor drivers pointless. Using mouse models for Shh medulloblastoma and
primary cultures of cerebellar granule neuron progenitor (CGNPs) cells, proposed to be Shh medulloblastoma
cells-of-origin, we have made the observation that the oncogenic DNA- and RNA-binding protein YB1 promotes
DNA repair after radiation. We have also observed that YB1 localizes to the perivascular niche (PVN) tumor
cells in mouse and human medulloblastoma. These cells are known for their radiation resistant properties. We
have also observed that HIF1a, whose mRNA translation is promoted by YB1, is likewise found in the PVN,
where we hypothesize that it promotes maintenance of the stem cell-like phenotype, which also confers radiation
resistance. HIF1a is normally degraded under normoxic conditions, however our preliminary studies indicate
that it is stabilized in a reactive oxygen species (ROS) and NADPH oxidase (Nox4)-dependent manner. Here,
we propose to use mouse Shh medulloblastoma models to test the hypothesis that pharmacologically targeting
YB1 in vivo can induce tumor cell death in the perivascular niche, and that in vitro and in vivo treatment of mouse
medulloblastoma with inhibitors of ROS or NADPH oxidase will destabilize HIF1a and similarly increase radiation
response. Finally, we propose a translational aim wherein we will utilize a novel microfluidic drug delivery
platform to test the combined effects of YB1 and ROS inhibition on cell viability in freshly resected human
medulloblastoma tumor slices, along with analysis of HIF1a, YB1, and Nox4 localization in primary and recurrent
medulloblastoma specimens from a newly established biorepository at Children’s Hospital of Atlanta. Our
studies have the potential to validate YB1 activity and HIF1a stabilization as novel therapeutic targets in
medulloblastoma, and to set a precedent for screening pat...

## Key facts

- **NIH application ID:** 9998031
- **Project number:** 5R01NS110386-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Anna Marie Kenney
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $341,500
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998031

## Citation

> US National Institutes of Health, RePORTER application 9998031, Y-Box 1 and normoxic HIF1 in Sonic hedgehog medulloblastoma tumor stem cell radiation resistance (5R01NS110386-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9998031. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*