# Targeting CD44 signaling in regulating glioblastoma stemness and immune response

> **NIH NIH R21** · AUGUSTA UNIVERSITY · 2023 · $235,979

## Abstract

Project summary
Glioblastoma (GBM) is the most frequent brain tumor with a very poor prognosis. Currently, despite surgery,
chemotherapy, and radiotherapy as the standard-of-care treatments, combination of these regimens does not
prolong patient survival significantly. Oncolytic viral therapy opens a new era for solid tumor therapy, especially
for brain tumors. HSV-1 derived oncolytic viruses (oHSVs) are the most advanced type of oncolytic virus (OV)
and the only type of virus that is currently FDA approved in the USA. Very recently, another oHSV (Delytact,
marketed by Daiichi) was granted conditional approval for the treatment of GBM patients in Japan. Thus,
investigating ways to improve oHSV therapy against GBM is highly significant. However, the anti-tumor efficacy
of oncolytic virus (OV) is limited by tumor microenvironment (TME). CD44 signaling regulates GBM TME through
interaction with extracellular matrix (ECM) or immune cells. Hyaluronic acid is one of the key extracellular matrix
components derived from glucose metabolites in GBM. CD44 is highly expressed in GBM cells and is a marker
for glioblastoma stem cells (GSCs). CD44 also bind to other ligands, such as, osteopontin (OPN), chrondroitin
and proteoglycan to regulate ECM and immune cell function.
Our ongoing experiments show that: 1) CD44 expression in GBM is correlated with poor prognosis of patients,
2) Oncolytic herpes simplex virus type 1 (oHSV) intratumoral injection increases HA secretion in brain tumor
xenografts in vivo, 3) oHSV-CD44 significantly downregulates SOX2 and decreases stemness of GSCs, 4)
oHSV-CD44 significantly increases anti-tumor efficacy in vivo, and 5) Combination oHSV-CD44 with an AKT
inhibitor or irradiation could further decrease SOX2 and Nestin expression in GSCs and reduce GSC stemness.
Given these findings, we hypothesize that blocking CD44 signaling in tumor microenvironment (TME) using a
CD44 extracellular domain-secreting oncolytic virus (oHSV-CD44) will not only disable CD44-mediated GBM
growth and lead to immunosuppression but will also inhibit GSC stemness while sensitizing the cells to
chemotherapy and radiotherapy. The hypothesis will be addressed with the following experiments proposed in
the Specific Aims: 1) Investigate whether combination oHSV-CD44 with an AKT inhibitor reduces GSC stemness
and increases the anti-GBM immune response, and 2) Test whether oHSV-CD44 increases radiotherapy-
mediated anti-GBM efficacy.
The proposed study is significant and has a broad impact on several research areas. In addition to shedding
light on the fundamental understanding of HA-CD44 signaling in GSCs stemness, GBM invasiveness, and
standard-of-care treatment sensitivity, this study will uncover the role of CD44 signaling blockade by oHSV-CD44
in enhanced efficacy of GBM treatment, including chemotherapy or radiotherapy. Furthermore, combination of
oHSV-CD44 with an AKT inhibition or radiotherapy will provide novel treatment strategies for tumor relapse.

## Key facts

- **NIH application ID:** 10742393
- **Project number:** 1R21NS130429-01A1
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** Bangxing B Hong
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $235,979
- **Award type:** 1
- **Project period:** 2023-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10742393

## Citation

> US National Institutes of Health, RePORTER application 10742393, Targeting CD44 signaling in regulating glioblastoma stemness and immune response (1R21NS130429-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10742393. Licensed CC0.

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