# Polyamines drive glioblastoma progression

> **NIH NIH F31** · CLEVELAND CLINIC LERNER COM-CWRU · 2022 · $37,941

## Abstract

PROJECT SUMMARY
Glioblastoma (GBM) is the most prevalent primary malignant brain tumor and is highly lethal with a median
survival of approximately 20 months. GBM is incurable despite aggressive standard treatment with radiation,
surgical resection and chemotherapy. The resistance of GBM to therapy is due to multiple factors, including
tumor heterogeneity, diffuse tumor growth, and a highly immunosuppressive environment. Naturally occurring
polyamines (PAs) have been found in increased levels in GBM patients. PAs have been identified as a potential
therapeutic target in several other types of cancers but have yet to be studied in the context of GBM. Under
normal conditions, PAs contribute to cell growth and proliferation as well as maintain cell health through
autophagy. Further studies are needed to understand methods of action of PA contribution in GBM. Additionally,
PAs are also consumed in diet and produced by several bacterial strains present in the gut microbiota. The gut
microbiome has surfaced as a prominent influence on immune system responses to disease. Cytokines and
metabolites produced by gut bacteria can enter the bloodstream and interact with peripheral immune cells as
well as the tumor microenvironment. PAs specifically affect cytokine production, altering the immune response
and providing an immune link between the gut microbiota and cancer. Gut dysbiosis reduces the efficacy of
immunotherapies such as immune checkpoint inhibitors in lung cancer. The mechanisms through which PAs
drive GBM progression need to be investigated and whether this pathway can be harnessed for therapy. PAs
are of particular interest as they can be produced both by tumor cells as well as by the microbiome and it is
unclear how each source may contribute to GBM growth. Preliminary data I have obtained provides evidence
that PAs decrease survival in mouse GBM models and in vitro analysis revealed PAs inhibit several immune cell
populations. Based on these observations, I hypothesize that PAs drive GBM growth via intrinsic cellular
mechanisms as well as the gut-brain-microbiome axis. This hypothesis will be tested in two experimental aims.
Aim 1 will test the hypothesis that tumor-derived PAs drive GBM growth by promoting an immunosuppressive
environment and will focus on the tumor cell intrinsic response to PA. Aim 2 will test the hypothesis that PAs
absorbed from diet or produced by gut microbes drive GBM progression and decrease survival and will focus on
the tumor cell extrinsic/systemic response to PA. These aims will be accomplished through a series of in vivo
experiments in immune competent and germ-free GBM mouse models, as well as an in vitro investigation of
molecular mechanisms. The short-term impact of this project is the elucidation of gut microbiome effects on
GBM, using the function of PA as a paradigm. The long-term impact of this project is the development of
therapies that target gut-brain-microbiome axis pathways in order to more effective...

## Key facts

- **NIH application ID:** 10534101
- **Project number:** 5F31CA264849-02
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Kristen Kay
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $37,941
- **Award type:** 5
- **Project period:** 2021-07-26 → 2024-07-25

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10534101

## Citation

> US National Institutes of Health, RePORTER application 10534101, Polyamines drive glioblastoma progression (5F31CA264849-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10534101. Licensed CC0.

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