# Defining the role of cytomegalovirus in glioblastoma therapies

> **NIH NIH R01** · BROWN UNIVERSITY · 2022 · $688,910

## Abstract

Project Summary/Abstract
Glioblastoma (GBM) is an incurable brain tumor for which improved therapies are badly needed. There are
roughly 10,000 cases diagnosed in the US each year, and median survival is ~14 months. Evidence has been
accumulating over recent years linking cytomegalovirus (CMV) to GBM and other cancers. However, the role
of CMV in GBM remains poorly defined. CMV is a prevalent virus in humans, where it resides lifelong in a
latent state but can be reactivated under certain conditions. Several clinical trials targeting CMV using diverse
approaches including immunotherapies and the anti-viral drug CMV have shown very promising responses in
GBM patients, but the underlying mechanisms are not clear. To improve our understanding of this area we
have developed an immunocompetent murine model of intracranial GBM grown in the context of a systemic
latent CMV infection. This consistently leads to significantly shortened survival compared with mock infected
controls in multiple distinct murine GBM models. These effects can be reversed by treatment with anti-viral
drugs. Our new preliminary human data shows reduced progression free survival in CMV seropositive humans
and similarities in patterns of differentially expressed genes supporting the relevance of the mouse model. Our
model features increased blood vessel formation, with accumulation of perivascular pericytes, increased CD8+
T cell infiltrates and resistance to chemotherapy. We discovered that platelet-derived growth factor-δ (PDGFD)
is upregulated by CMV infection of tumor cells, and that CRISPR-mediated knockdown of PDGFD prevents
pericyte recruitment and severely impairs tumor growth. Therefore in Specific Aim 1 we will further
investigate PDGFD as a potential GBM therapeutic target. Also, we have preliminary data with a replication-
defective viral mutant suggesting that CMV replication is critical to this phenotype, and we will use this mutant
to explore the mechanisms by which CMV enhances tumor progression. We also have shown that the tumor
microenvironment is significantly impacted by CMV, therefore in Specific Aim 2 we will examine the
therapeutic implications of CMV on tumor/immune interactions, and the importance of viral replication in these
effects. In Specific Aim 3 we will use our model to investigate the interactions of CMV with standard of care
chemoradiation, in terms of viral reactivation and sensitization to therapies by anti-viral drugs. Results from the
proposed experiments will bring us to a deeper understanding of the impact that CMV has on GBM
progression, providing badly needed targets and rational therapeutic combinations for future clinical trials in
this devastating disease.

## Key facts

- **NIH application ID:** 10443072
- **Project number:** 1R01CA263324-01A1
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** CHARLES H COOK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $688,910
- **Award type:** 1
- **Project period:** 2022-04-11 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10443072

## Citation

> US National Institutes of Health, RePORTER application 10443072, Defining the role of cytomegalovirus in glioblastoma therapies (1R01CA263324-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10443072. Licensed CC0.

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