# Cellular and Molecular Origins of Medulloblastoma Subgroups

> **NIH NIH P01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $183,624

## Abstract

Summary – Project 4 
Medulloblastoma encompasses four molecular subtypes that have different prognoses (WNT, Sonic Hedgehog 
[SHH], Group-3 and Group-4). Despite these differences, all children with medulloblastoma receive the same 
surgery, radiation, and chemotherapy. This treatment fails to cure most cases of Group-3 disease, and inflicts 
debilitating long-term side effects on children with WNT-medulloblastoma. Therefore, future efforts to cure all 
children with medulloblastoma must provide an understanding of disease biology that can guide the 
development of curative, relatively non-toxic, subtype-specific therapies. During the last funding cycle we 
focused on understanding WNT-medulloblastoma, complementing studies by our P01 colleagues of the other 
disease subtypes. We identified progenitor cells of the lower rhombic lip as the origin of WNT- 
medulloblastoma, and generated the first mouse model of this disease subtype. In addition, using whole 
genome sequencing (WGS), we identified over 40 novel mutations in medulloblastoma, including highly 
recurrent mutations in a new candidate oncogene of WNT and SHH-tumors, DDX3X. The proposed studies will 
build on these data, and through three new Specific Aims will address our central hypothesis: 
`Medulloblastoma subtypes are driven by distinct cell signals that can be targeted for therapeutic gain.' 
Through a comprehensive series of in vitro and in vivo phenotype and tumorigenesis assays, Aim 1 will 
determine the role of DDX3X in hindbrain development and medulloblastoma. Aim 2 will employ an innovative, 
multiplatform approach that integrates high-throughput drug screening, cell biology assays, and genomics to 
pinpoint key molecular therapeutic targets and matched inhibitors of WNT-medulloblastoma, including DDX3X. 
Aim 3 will test the subtype-specificity of potential new therapies identified in Aim 2 in the context of novel, 
combination, neurosurgical, irradiation, and chemotherapy trials in mice with WNT, SHH and Group-3 tumors. 
In this manner we will perform the most rigorous preclinical testing of new subtype-specific treatments of 
medulloblastoma to date, and thereby optimize the selection of combination treatments for translation to 
clinical trial.

## Key facts

- **NIH application ID:** 10230058
- **Project number:** 3P01CA096832-15S1
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Richard James Gilbertson
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $183,624
- **Award type:** 3
- **Project period:** 2002-07-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10230058

## Citation

> US National Institutes of Health, RePORTER application 10230058, Cellular and Molecular Origins of Medulloblastoma Subgroups (3P01CA096832-15S1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10230058. Licensed CC0.

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