# Inducing neural maturation in medulloblastoma by targeting EZH2

> **NIH NIH R56** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $460,937

## 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 negative side effects of radiation therapy to the growing and developing
child's brain. Survivors suffer from memory and 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 are able to 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 that resembles neuronal differentiation
processes that occur during normal brain development. We hypothesize that spontaneous maturation is
epigenetically driven and 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 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:** 10416148
- **Project number:** 1R56NS122987-01
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Praveen B. Raju
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $460,937
- **Award type:** 1
- **Project period:** 2021-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10416148

## Citation

> US National Institutes of Health, RePORTER application 10416148, Inducing neural maturation in medulloblastoma by targeting EZH2 (1R56NS122987-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10416148. Licensed CC0.

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