# Inducing Neural Maturation in Medulloblastoma by Targeting EZH2

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $672,469

## Abstract

PROJECT SUMMARY/ABSTRACT
Medulloblastoma is the most common pediatric brain tumor and accounts for approximately 20% of all brain
tumors in children. Medulloblastoma is highly malignant and difficult to treat, resulting in nearly 30% of affected
patients being incurable. Additionally, even children that are cured suffer from severe long-term deficiencies
primarily due to the adverse side effects of radiation therapy on the growing and developing child's brain.
Survivors suffer from memory, attention deficits, decreased IQ, cognitive and learning disabilities, thyroid and
gonadal dysfunction (infertility), and growth delay. It is estimated that fewer than 20% of medulloblastoma
survivors who reach adulthood can live independent lives. Therefore, more effective and less toxic therapies
are greatly needed for patients with medulloblastoma.
While medulloblastoma is composed of primitive undifferentiated neuroblasts, some tumors show foci of
spontaneous maturation into a non-proliferative brain-like tissue resembling neuronal differentiation processes
during normal brain development. We hypothesize that spontaneous maturation is epigenetically driven; by
elucidating the drivers of spontaneous maturation, novel therapeutic avenues can be identified that will allow
us to induce maturation in the clinic and force the malignant tumor into benign brain-like tissue. We show that
mature and primitive areas in medulloblastoma have distinctly different RNA expression patterns and that
PRC2 is a master regulator of this process in human tissue samples and animal models.
In this proposal, we aim to hijack neurodevelopmental processes for therapy of MB by exploring the
mechanism of spontaneous maturation to identify the pathways regulated by PRC2 through the following
specific aims: 1) Integrating molecular dissection of epigenetic machinery and transcriptomics in mature and
primitive components of human medulloblastoma, 2) Elucidate the role of EZH2 in epigenetic regulation of
tumor cell maturation in mouse SHH MB, and 3) Assess the efficacy and toxicity of tumor vasculature- targeted
EZH2 and Sonic hedgehog (SHH) pathway inhibition in SHH-driven medulloblastoma. We will utilize high-
resolution genomics and epigenetics techniques, a genetically relevant mouse medulloblastoma model that
recapitulates the human disease, and a novel tumor vasculature-specific nanoparticle drug delivery platform
that allows penetration past the blood-brain barrier.
Our long-term objective is to identify tumor-selective epigenetic strategies to induce spontaneous maturation
that synergize with the current standard of care therapies for medulloblastoma. Should our results prove
favorable, we envision applicability to patients with medulloblastoma and other brain tumors.

## Key facts

- **NIH application ID:** 10906296
- **Project number:** 5R01NS122987-03
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Praveen B. Raju
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $672,469
- **Award type:** 5
- **Project period:** 2022-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906296

## Citation

> US National Institutes of Health, RePORTER application 10906296, Inducing Neural Maturation in Medulloblastoma by Targeting EZH2 (5R01NS122987-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10906296. Licensed CC0.

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