# Extracellular Vesicles (EVs) and Genes in the Biology and Therapy of Gliomas

> **NIH NIH P01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $1,316,276

## Abstract

Glioblastoma multiforme (GBM) has an abysmal prognosis despite advances in genomics, new targeted
therapies, and increased understanding of its pathobiology. The goal of our Program Project Grant (PPG) is to
improve knowledge about GBM biology and develop effective therapies. Investigators in this PPG have made
two notable advances, among many: 1- Tumor extracellular vesicles (tEVs) and their contents transfer
functional information among cells in the GBM microenvironment, thereby increasing oncogenic behaviors, and
2- a Phase II clinical trial in patients with newly diagnosed GBM utilizing Gene-mediated Cytotoxic
Immunotherapy (GMCI) as an adjuvant to standard-of-care (SOC) has shown encouraging, albeit non-
definitive, results. The major hypotheses of this PPG's competitive renewal are that GBM therapy can be
improved by combining SOC and GMCI with immune checkpoint inhibition, and that therapeutic responses can
be monitored in biofluids by assessing protein and RNA content in tEVs. Three synergistic projects and three
supporting cores will test these hypotheses. Project 1 (Xandra Breakefield) will evaluate whether glioma EVs
and their contents are fundamental regulators of glioma heterogeneity within the tumor and immune
suppression in the tumor microenvironment, thus contributing to tumor progression, immuno-evasion, and
therapeutic resistance. Project 2 (Ralph Weissleder) will validate novel technological advances from his
laboratory, such as single EV analysis (SEA), to assay tEV contents in biofluids, thus overcoming the limitation
of scant materials available from preclinical and clinical trials. Project 3 (E. Antonio Chiocca) will test if
SOC/GMCI combined with immune checkpoint inhibition will be an effective therapy in preclinical models of
glioma and, ultimately, in a randomized clinical trial. Core A (Breakefield/Chiocca) will provide the necessary
administrative structure, scientific oversight, and overall leadership functions for the PPG, including basic
science (Breakefield) and preclinical/clinical (Chiocca) efforts. Core B (Carter) will maintain the Clinical
Sample Core that biobanks cerebral spinal fluid and serum/plasma samples from patients and clinical trials for
tEV analysis, as well as serve as the biostatistics resource. Core C (Charest) will provide genetically
engineered mouse models of gliomas and mouse/human glioma “stem-like” cells from different GBM subtypes.
Together these investigators will generate the necessary scientific justification and preclinical data to ultimately
support the proposed clinical trial of GMCI with immune checkpoint inhibition in newly diagnosed GBM
patients, in which tEVs will be evaluated for their potential as biomarkers and modulators of the therapeutic
response.

## Key facts

- **NIH application ID:** 9939458
- **Project number:** 5P01CA069246-23
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** XANDRA OWENS BREAKEFIELD
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,316,276
- **Award type:** 5
- **Project period:** 1997-06-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939458

## Citation

> US National Institutes of Health, RePORTER application 9939458, Extracellular Vesicles (EVs) and Genes in the Biology and Therapy of Gliomas (5P01CA069246-23). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9939458. Licensed CC0.

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