# Project 2: Biological mechanisms and therapeutic vulnerabilities underlying meningioma evolution and heterogeneity

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $480,584

## Abstract

PROJECT 2: PROJECT ABSTRACT
 The World Health Organization (WHO) has historically graded meningiomas according to histological
features, and many WHO grade 1 meningiomas can be effectively treated with surgery or radiotherapy, but many
WHO grade 2 or grade 3 meningiomas are resistant to treatment and cause significant neurological morbidity
and mortality. Approximately 30% of WHO grade 1 meningioma develop recurrences that cannot be predicted
from histological features, and some WHO grade 2 or grade 3 meningiomas are unexpectedly well controlled
with surgery and radiotherapy. These data indicate that improvements in risk stratification and new therapies for
patients with meningiomas are needed, but limited understanding of meningioma biology and the misconception
that all meningiomas are benign has encumbered medical and scientific advances for patients with meningiomas.
 Using multiplatform molecular profiling on 2092 meningiomas from 13 institutions, we discovered DNA
methylation groups and a gene expression biomarker that improve risk stratification compared to all other
classification systems across all WHO grades. Our data demonstrate that meningiomas from the DNA
methylation group with the worst outcomes are vulnerable to cell cycle inhibitors (28%), and that gene expression
profiling predicts which meningiomas will benefit from postoperative radiotherapy (32%). Cooperative group
trials, clinical guidelines, and classification systems that incorporate our DNA methylation and gene expression
biomarkers are under development. More broadly, our biomarkers provide a framework for understanding how
meningiomas grow and respond to therapy, but biomarkers that are based on one sample from a single point in
time may not be optimal. Here we propose to study (1) biological drivers, (2) imaging features, and (3) therapeutic
vulnerabilities underlying DNA methylation and gene expression biomarkers using regionally distinct samples
from individual meningiomas (Aim 1), patient-matched meningioma samples over time (Aim 2), and an organoid
model of meningioma heterogeneity integrated with a novel functional genomic technique (Aim 3).
 Our central hypothesis is that understanding how meningiomas grow and respond to therapy will (1) identify
drivers underlying meningioma biomarker performance to optimize risk stratification, (2) define magnetic
resonance (MR) imaging features of meningioma biomarkers to establish a foundation for non-invasive risk
stratification, and (3) inform future therapies to improve the care of patients with the most common primary
intracranial tumor. Our studies will use bulk, single-cell, spatial, and functional genomics to investigate
meningioma evolution and heterogeneity in the context of intratumor or whole tumor MR imaging features. To
do so, we have assembled a biobank 367 patient-matched meningioma samples from 156 patients who were
treated with serial surgery ± radiotherapy, 27 patient-derived meningioma cell lines that repre...

## Key facts

- **NIH application ID:** 10934265
- **Project number:** 2P01CA118816-16
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** David R Raleigh
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $480,584
- **Award type:** 2
- **Project period:** 2007-07-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10934265

## Citation

> US National Institutes of Health, RePORTER application 10934265, Project 2: Biological mechanisms and therapeutic vulnerabilities underlying meningioma evolution and heterogeneity (2P01CA118816-16). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10934265. Licensed CC0.

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