# Determining the role of lipid droplets in glioblastoma and their therapeutic potential

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $408,589

## Abstract

ABSTRACT
Glioblastoma (GBM) is the most aggressive brain tumor, and has a median survival of only 12-15 months despite
intensive therapies, indicating the urgent need to identify effective approaches to treat GBM and circumvent
resistance to therapies in order to significantly improve patient survival. Our recent studies demonstrated that
lipid synthesis and uptake are greatly enhanced in GBM and promote tumor growth. It is known that increased
free fatty acids (FFA) and cholesterol can cause endoplasmic reticulum (ER) stress and lipotoxicity that lead to
cell death, which raises the intriguing question of how GBM cells can prevent the toxicity potentially induced by
increased lipid metabolism. We recently found that tumor tissues from GBM patients contain large amount of
lipid droplets (LDs), triglycerides (TG) and cholesteryl esters (CE), suggesting that GBM cells may store excess
FFA and cholesterol into LDs to avoid toxicity and maintain tumor growth. Further analysis showed that GBM
patients whose tumor tissues contained higher levels of LDs and of DGAT1 (diglyceride acyltransferase) or
SOAT1 (sterol O-acyltransferase), two ER membrane-bound enzymes that catalyze the conversion of excess
FFA and cholesterol into TG and CE to form LDs, had the worse survival, suggesting that LDs may have a
protumoral function. Consistent with our findings, several groups have recently reported that inhibiting cholesterol
esterification or suppressing LD formation in prostate, pancreatic or renal cancer cells significantly enhanced ER
stress. Nevertheless, many important LD functions in cancer cells remain unexplored, such as their
energetic role and potential for supporting tumor resistance. Our preliminary data suggest that LDs may
provide a critical energy source for GBM survival under nutrient reduction or radiation/temozolomide (TMZ)
treatment, the standard therapy for GBM. Based on current understanding of LDs in cancer cells and our novel
preliminary data, we hypothesize that LD formation in GBM prevents ER stress and lipotoxicity, and also serves
as energy reservoir to support tumor survival upon energy challenges. We further hypothesize that inhibiting
LD formation will cause ER stress, lipotoxicity and energy shortage, which may strongly synergize with
radiation/TMZ treatment to induce GBM cell death. In this study, we will: (1) delineate the underlying protective
role of LD formation in GBM cells; (2) determine whether LDs play an important energetic role in GBM cells; (3)
examine whether genetically or pharmacologically inhibiting LD formation effectively suppresses tumor growth
and sensitizes GBM to radiation/TMZ treatment in GBM orthotopic mouse models. This study will reveal the
previously uncharacterized role and molecular regulation of LDs in GBM. Importantly, it will also demonstrate
that inhibiting LD formation may be a very effective approach to specifically target GBM with little toxicity on
normal brain tissues where no LDs could be detec...

## Key facts

- **NIH application ID:** 10201766
- **Project number:** 5R01NS104332-04
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Deliang Guo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $408,589
- **Award type:** 5
- **Project period:** 2018-09-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201766

## Citation

> US National Institutes of Health, RePORTER application 10201766, Determining the role of lipid droplets in glioblastoma and their therapeutic potential (5R01NS104332-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10201766. Licensed CC0.

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