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

Award Number: R01NS104332
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Determining the role of lipid droplets and their therapeutic potential in glioblastoma - ABSTRACT Over the past two decades, the prognosis for glioblastoma (GBM), the most lethal brain tumor, has remained dismal, with a median survival of only 12-16 months from diagnosis. We recently demonstrated that GBM cells acquire large amounts of fatty acids (FAs) and cholesterol by dramatically upregulating their de novo synthesis and uptake for rapid tumor growth. However, excess FAs and cholesterol can alter membrane dynamics and function, leading to cellular damage. How GBM cells avoid this lipotoxicity to sustain proper lipid levels in different cellular compartments, particularly in the mitochondria, is poorly understood. During the past 5 years of funding, we have made great progress in understanding how GBM controls FA homeostasis. We demonstrated that GBM cells upregulate diacylglycerol acyltransferase 1 (DGAT1), allowing them to store abundant FAs as triacylglycerol-containing lipid droplets (LDs) to prevent excess FA accumulation to induce toxicity. In this renewal proposal, we will address two unanswered critical questions: 1) how is cholesterol homeostasis regulated in GBM cells? and 2) can effective therapeutic approaches be developed for GBM by disrupting lipid homeostasis? We recently found that cholesteryl esters (CEs), which form LDs to store excess cellular cholesterol, are largely present in GBM tissues, and blocking CE synthesis results in dramatic mitochondrial fragmentation in GBM cells. Moreover, our preliminary data showed that cholesterol is transferred from CE- containing LDs (CE-LDs) to the plasma membrane, while inhibition of autophagy blocks this transfer. These data suggest that CE-LDs maintain proper cellular cholesterol levels via autophagy. Our preliminary data further showed that stearoyl-CoA desaturase 1 (SCD1), which has been shown to prevent endoplasmic reticulum (ER) stress and ferroptosis, is upregulated upon DGAT1 inhibition. Finally, preliminary data showed that the expression of multiple antioxidant genes is significantly elevated in response to DGAT1 inhibition. These results strongly suggest that GBM cells can activate defense mechanisms to alleviate the lipotoxicity triggered by disruption of FA storage, possibly leading to tumor resistance to DGAT1 inhibition. Thus, we hypothesize that CE-LDs serve as critical reservoirs for controlling cholesterol homeostasis and mitochondrial function, and that combining disruption of storage or redistribution of cholesterol with interference with mitochondrial cholesterol import, or disruption of FA storage with either inhibition of SCD1 or blockade of antioxidant pathways are effective strategies for targeting GBM. In Aim 1, we will examine the impact of inhibiting cholesterol storage or redistribution from CE-LDs on cholesterol homeostasis and mitochondrial function, and whether such blockade can synergize with interfering in cholesterol import into mitochondria to efficiently kill tumor cells in GBM xenograft models. In Aim 2, we will examine whether inhibiting SCD1 or antioxidant pathways can strongly synergize with DGAT1 inhibition to effectively inhibit GBM growth in vitro and in vivo. Successful completion of this study will provide strong pre-clinical data on potential novel strategies to target GBM.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $544,245 )
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	6/27/2025	NON-COMPETING CONTINUATION	$544,245
2025	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $544,245

Issue Date FY: 2024 ( Subtotal = $527,917 )
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	7/16/2024	NON-COMPETING CONTINUATION	$527,917
														Subtotal = $527,917

Issue Date FY: 2023 ( Subtotal = $558,620 )
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	7/12/2023	COMPETING CONTINUATION	$558,620
														Subtotal = $558,620

Issue Date FY: 2022 ( Subtotal = $408,589 )
2022	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/23/2022	NON-COMPETING CONTINUATION	$408,589
														Subtotal = $408,589

Issue Date FY: 2021 ( Subtotal = $408,589 )
2021	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/17/2021	NON-COMPETING CONTINUATION	$408,589
														Subtotal = $408,589

Issue Date FY: 2020 ( Subtotal = $408,589 )
2020	2020	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/24/2020	NON-COMPETING CONTINUATION	$408,589
														Subtotal = $408,589

Issue Date FY: 2019 ( Subtotal = $408,589 )
2019	2019	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/1/2019	NON-COMPETING CONTINUATION	$408,589
														Subtotal = $408,589

Issue Date FY: 2018 ( Subtotal = $407,145 )
2018	2018	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/6/2018	NEW	$407,145
														Subtotal = $407,145

Grand Total All Awards = $3,672,283

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

Award Number: R01NS104332

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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