# Metabolic Resistance to Hypoxia in Glioblastoma Multiforme

> **NIH NIH F30** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $41,405

## Abstract

Abstract
The malignant brain tumor Glioblastoma (GBM) is a tragic illness for patients and families due to poor patient
prognosis, with only 9.8% of patients surviving past 5 years. Only modest gains in survival have been made
despite decades of research, therefore, a better understanding of the basic biology of this disease is needed to
improve patient outcomes. Hypoxia is characteristic of GBM and many other tumors, and is increased by the
anti-angiogenic agent bevacizumab, which is commonly used for recurrent GBM tumors. Metabolic changes
contribute to adaptation to tumor hypoxia, and can be potentially targeted to reduce treatment resistance. Our
preliminary data shows elevated levels of triglycerides and decreased levels of very long chain fatty acids in
highly hypoxic tumors. This suggests the use of peroxisomal fatty acid oxidation which primarily catabolizes very
long chain fatty acids, as a fuel source in highly hypoxic tumors. In addition, previous studies show that hypoxia
induces secretion of triglyceride-loaded extracellular vesicles in prostate cancer cells. Triglyceride-loaded
extracellular vesicles may be a potential mechanism for delivering fuel sources to GBM cells during hypoxia. We
hypothesize that GBM cells rely on peroxisomal fatty acid oxidation and triglyceride-loaded extracellular vesicle
secretion to fuel tumor growth during hypoxia. We will investigate this hypothesis through our specific aims: 1)
determine the effect of peroxisomal fatty acid oxidation in adaptation to hypoxia induced by anti-angiogenic
treatment in GBM tumors, and 2) define the role of extracellular vesicle formation and lipid secretion in adaptation
to hypoxia induced by anti-angiogenic treatment in GBM tumors. To address both of these specific aims, we will
1) determine the lipid metabolism effects of hypoxia on cells and extracellular vesicles in vitro using
metabolomics and mRNA analysis, and 2) test the efficacy of combining inhibitors targeting peroxisomal fatty
acid oxidation or triglyceride synthesis with anti-angiogenic treatment both in vitro and in vivo. When using these
inhibitors, we expect to see 1) inhibition of cell growth in vitro in cells exposed to hypoxia, and 2) inhibition of
tumor growth and extension of survival for tumors treated with anti-angiogenic treatment and our inhibitory
agents, compared to either treatment alone. These studies are significant in that they will elucidate mechanisms
for tumor growth and resistance to treatment. The identified mechanisms can be targeted and incorporated into
innovative treatment regimens for GBM patients, potentially leading to substantial increases in survival and
patient well-being.

## Key facts

- **NIH application ID:** 9875448
- **Project number:** 5F30CA225143-03
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Laura Caflisch
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $41,405
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9875448

## Citation

> US National Institutes of Health, RePORTER application 9875448, Metabolic Resistance to Hypoxia in Glioblastoma Multiforme (5F30CA225143-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9875448. Licensed CC0.

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