# Prevention and treatment of lethal metastases in group 3 medulloblastoma

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $566,684

## Abstract

Brain tumors are the most common solid tumor and the leading cause of cancer-related death in children.
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Dissemination (metastasis) of MB results in
seeding the leptomeningeal membranes that cover the brain and spinal cord. In prior work, we demonstrated that
metastases are biologically distinct from their matched primary tumor that metastases are the overwhelming cause of
death in children with MB, and that metastatic disease which frequently develops post-therapy is highly clonally divergent
to therapy naïve metastases. Group 3 medulloblastoma (G3 MB) is responsible for the majority of deaths among MB
patients. While only a third of G3 MB patients have visible metastases at diagnosis, almost 100% of patients with
recurrent disease have metastases. The major source of morbidity in MB survivors is irradiation of the entire developing
brain and spinal cord, performed to prevent metastatic recurrence, but leaving survivors with cognitive delay, growth
failure, and secondary cancers. Modest decreases in the dose of craniospinal radiation would significantly improve quality
of life for survivors. Understanding the biological basis of leptomeningeal dissemination, progression, and recurrence in
G3 MB could therefore allow the development of therapies to supplement craniospinal radiation, enabling radiation dose
reductions without an increased rate of recurrence. We have shown previously that, whereas most SHH tumors recur
locally, G3 almost always recurs metastatically. This proposal leverages a well-validated GEMM model of G3 MB made
collaboratively in the PIs labs, to discover genes that drive up-front metastatic initiation/progression and metastatic
recurrence after radiation therapy. Identifying these genes should enable us to test novel therapies in a mouse hospital
setting, to prevent metastatic recurrence in the setting of reduced craniospinal radiation. Our aims are to:
Aim 1. Discover genes and pathways that initiate and drive progression of up-front metastases in G3 MB utilizing our
animal model (functional genomics), followed by validation in human samples (cancer genomics) and functional
validation using in vivo mouse models.
Aim 2. Discover genes and pathways that initiate and drive progression of post-treatment metastases in G3 MB in
response to radiation. We will use functional genomics and cancer genomics in a humanized mouse hospital setting,
delivering both microneurosurgery and image guided multifractionated craniospinal radiotherapy.
Aim 3. Initiate murine clinical trials to prophylactically prevent metastatic recurrence of G3 MB after surgery and reduced
dose craniospinal irradiation, through delivery of novel agents targeting of mTOR, aneuploidy, and additional targets
discovered in Aims #1 and #2.

## Key facts

- **NIH application ID:** 10007915
- **Project number:** 5R01NS106155-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Michael D. Taylor
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $566,684
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10007915

## Citation

> US National Institutes of Health, RePORTER application 10007915, Prevention and treatment of lethal metastases in group 3 medulloblastoma (5R01NS106155-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10007915. Licensed CC0.

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