# Targeting Hyaluronan-mediated Motility Receptor in Glioblastoma Stem Cells

> **NIH NIH R01** · HUGO W. MOSER RES INST KENNEDY KRIEGER · 2020 · $353,543

## Abstract

Glioblastoma multiforme (GBM) is the most aggressive and lethal primary brain tumor in humans. GBM stem
cells (GSCs) are a subpopulation of GBM tumor cells that show stem-cell-like properties and play a central role
in tumor propagation, therapeutic resistance and tumor recurrence. We need effective therapeutic strategies to
directly deplete GSCs and/or sensitize them to current GBM therapies. Developing these therapies relies on a
more complete understanding of molecular drivers of GSC tumorigenicity and therapeutic resistance. This
project focuses on targeting an oncogenic signaling pathway driven by the hyaluronan-mediated motility
receptor (HMMR) and its downstream effector TAZ, an oncogenic transcription factor. Our central hypothesis is
that HMMR and TAZ comprise a drug-targetable pathway that promotes GSC tumorigenicity and
radioresistance. We propose to fill major knowledge gaps in the function of HMMR-TAZ signaling in GSCs and
therapeutic applicability of HMMR-TAZ targeting in GBM. Our recent Cancer Research paper demonstrates
that HMMR is a potential therapeutic target for depleting GSCs. HMMR is hyper-expressed in clinical GBM
specimens. HMMR silencing effectively inhibits GSC self-renewal in vitro and tumorigenicity in vivo. Our
following studies found that HMMR forms a positive feedback loop with TAZ in GSCs. This HMMR-TAZ loop
signaling is essential for cell-intrinsic radioresistance in GSCs. More interestingly, HMMR-TAZ signaling also
induces the spreading of radioresistance among GSCs through paracrine mechanisms likely mediated by
secretory proteins. For clinical targeting of HMMR-TAZ signaling, we identified the FDA-approved drug
Verteporfin (VP) as an inhibitor of HMMR-TAZ signaling and GSC tumorigenicity. VP crosses the blood-tumor
barrier, supporting the feasibility to study systemic VP treatment in GBM models. Overall, our preliminary
studies justify a rigorous study of autocrine and paracrine mechanisms underlying HMMR-TAZ-driven
radioresistance in GSCs, and further determining the therapeutic synergy between HMMR-TAZ targeting and
radiation in pre-clinical GBM models. It is also necessary to extensively study the therapeutic efficacy of VP in
GSCs, molecular mechanisms of its drug action, and the therapeutic synergy between VP and radiation. We
will study two specific aims: (1) determine if targeting HMMR-TAZ signaling inhibits GSC radioresistance, and
further elucidate underlying molecular mechanisms, and (2) repurpose the FDA-approved drug Verteporfin to
target HMMR-TAZ signaling in GBM. If successful, Aim 1 will provide novel mechanistic insights into how
GBM-associated protein HMMR drives downstream transcriptional events to promote GSC tumorigenicity and
therapeutic resistance. We will reveal a novel paracrine mechanism that mediates the spreading of
radioresistance among GBM cells. Aim 2 will provide a solid foundation for repurposing VP for GBM therapy.
VP repurposing is a novel strategy for targeting HMMR-driven on...

## Key facts

- **NIH application ID:** 9961699
- **Project number:** 5R01NS099460-04
- **Recipient organization:** HUGO W. MOSER RES INST KENNEDY KRIEGER
- **Principal Investigator:** Mingyao Ying
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $353,543
- **Award type:** 5
- **Project period:** 2017-09-30 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9961699

## Citation

> US National Institutes of Health, RePORTER application 9961699, Targeting Hyaluronan-mediated Motility Receptor in Glioblastoma Stem Cells (5R01NS099460-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9961699. Licensed CC0.

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