# The power of extracellular vesicles in glioblastoma

> **NIH NIH R35** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $989,400

## Abstract

Project Summary/Abstract
Glioblastomas remain one of the most deadly cancers with no breakthroughs in therapy for the past 20 years.
Xandra Breakefield has made critical discoveries demonstrating that these tumor cells release extracellular
vesicles containing informative nucleic acids and proteins that convert normal brain cells to tumor supportive
cells. Working with a team of seasoned investigators she has continued to make breakthrough advances in the
use of these vesicles as biomarkers, in elucidating the means by which they subjugate microglia and other
cells in their microenvirons, and in exploring how they may be channeled for therapeutic purposes. This team
consisting of Drs. Breakefield, Joseph El Khoury/Suzanne Hickman (microglia experts), Thorsten Mempel (T
lymphocyte expert), Marike Broekman (neurosurgeon) and Casey Maguire (vector expert) will advance these
insights in three interrelated areas: biomarkers, cell-to-cell communication and therapy. Studies are designed
to increase sensitivity and reveal clinical correlates of RNA and protein in extracellular vesicle biomarkers from
serum/plasma with goals of early detection, informing therapeutic decisions and longitudinal evaluation. They
will explore how tumor extracellular vesicles participate in changing the phenotype of microglia, macrophages
and astrocytes in the tumor microenvirons, such that they become a “life support” system for the tumor in
defiance of therapy. These insights will be forged into new therapeutic concepts with a focus on engaging the
innate and adaptive immune systems to arm the brain against the tumor. This will include increasing cross
presentation of extracellular vesicle-derived tumor antigens via microglia to infiltrating T lymphocytes using co-
stimulatory molecules. Microglia associated with the tumor will be endowed with increased capacity to release
anti-microbial peptides, which are also anti-tumorigenic, to reawaken their sense of the presence of the tumor
and to down-regulate program death-ligands that exhaust cytotoxic T lymphocytes. Tumor-associated cells,
including reactive astrocytes, microglia and macrophages will be manipulated using systemically administered
adeno-associated virus and other vectors (which are clinically compatible) carrying transgene cassettes under
promoters that are strongly up-regulated in cells near the tumor, but not in the same cell types in other parts of
the brain. Vesicles produced by these cells will also be used to deliver therapeutic cargo to tumors cells to
provide sustained therapeutic impact. These studies acknowledge the cytoplasmic continuum of cancer among
all the cell types that make up the tumor mass, and strike at this supportive microenvironment which sustains
the tumor. Therapeutic strategies are designed to be combinatorial with standard-of-care without increasing
morbidity for this devastating disease that has defied current therapeutic approaches.

## Key facts

- **NIH application ID:** 10465288
- **Project number:** 5R35CA232103-05
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** XANDRA OWENS BREAKEFIELD
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $989,400
- **Award type:** 5
- **Project period:** 2018-09-06 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465288

## Citation

> US National Institutes of Health, RePORTER application 10465288, The power of extracellular vesicles in glioblastoma (5R35CA232103-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10465288. Licensed CC0.

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