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Developing therapeutic strategies to elicit metabolic synthetic lethality in glioblastoma

Award Number: R01NS110838
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Developing therapeutic strategies to elicit metabolic synthetic lethality in glioblastoma - ABSTRACT Glioblastoma (GBM) continues to be an invariably fatal malignancy with limited treatment options. Our laboratory studies tumor metabolism and its potential to serve as a novel therapeutic target. Through a series of investigations, our group has identified that the diverse tumor ecology implicit in this malignancy contributes to considerable intratumoral metabolic heterogeneity and dynamic metabolic reprogramming, allowing GBM cells to adapt and proliferate under diverse, microenvironmental stresses. Specifically, through integrative cross-platform analyses coupling metabolomics with genomics in patient-derived tumors, we identified enhanced fatty acid oxidization (FAO) as a metabolic node in GBM driven by a transcriptional program designed to import and utilize fatty acids from the tumor microenvironment. This metabolic phenotype was specific to the mesenchymal subtype in GBM and recapitulated in preclinical models. Functional analyses uncovered specific roles these fatty acids play in gliomagenesis, which are dependent upon nutrient availability. In a state of glucose deprivation, mesenchymal GBM cells utilize these exogenous fatty acids to serve as a vital, alternate source of ATP, whereas in nutrient favorable conditions, the intermediary metabolism of FAO acts as a metabolic cue to drive a transcriptional program supporting cellular proliferation and mesenchymal differentiation. Accordingly, inhibiting FAO in standard, nutrient rich conditions led to decreased proliferation, however, robust energetic stress and non-apoptotic cell death was observed in mesenchymal GBM cells in the context of glucose deprivation. In this application, we propose to extend these promising findings by defining molecular mechanisms governing enhanced FAO in GBM (Aim 1), delineating the multiple roles FAO may play in gliomagenesis in the context of this tumor’s diverse tumor ecology (Aim 2), and evaluate the translational potential for eliciting metabolic synthetic lethality in GBM through energetic stress (Aim 3).


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: 2024 ( Subtotal = $323,500 )
2024	2024	WILLIAM BEAUMONT HOSPITAL	26901 BEAUMONT BLVD # 6D	SOUTHFIELD	MI	48033	OAKLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	5/3/2024	NON-COMPETING CONTINUATION	$23,347
2024	2024	WILLIAM BEAUMONT HOSPITAL	3601 W 13 MILE RD	ROYAL OAK	MI	48073	OAKLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/7/2023	NON-COMPETING CONTINUATION	$300,153
														Subtotal = $323,500

Issue Date FY: 2023 ( Subtotal = $333,504 )
2023	2023	WILLIAM BEAUMONT HOSPITAL	3601 W 13 MILE RD	ROYAL OAK	MI	48073	OAKLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	2/1/2023	NON-COMPETING CONTINUATION	$33,351
2023	2023	WILLIAM BEAUMONT HOSPITAL	3601 W 13 MILE RD	ROYAL OAK	MI	48073	OAKLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/20/2022	NON-COMPETING CONTINUATION	$300,153
														Subtotal = $333,504

Issue Date FY: 2022 ( Subtotal = $333,504 )
2022	2022	WILLIAM BEAUMONT HOSPITAL	3601 W. THIRTEEN MILE RD	ROYAL OAK	MI	48073	OAKLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/19/2021	NON-COMPETING CONTINUATION	$300,153
2022	2022	WILLIAM BEAUMONT HOSPITAL	3601 W 13 MILE RD	ROYAL OAK	MI	48073	OAKLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	6/24/2022	NON-COMPETING CONTINUATION	$33,351
														Subtotal = $333,504

Issue Date FY: 2021 ( Subtotal = $336,769 )
2021	2021	WILLIAM BEAUMONT HOSPITAL	3601 W. THIRTEEN MILE RD	ROYAL OAK	MI	48073	OAKLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/26/2021	NON-COMPETING CONTINUATION	$33,678
2021	2021	WILLIAM BEAUMONT HOSPITAL	3601 W. THIRTEEN MILE RD	ROYAL OAK	MI	48073	OAKLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/16/2020	NON-COMPETING CONTINUATION	$303,091
														Subtotal = $336,769

Issue Date FY: 2020 ( Subtotal = $341,614 )
2020	2020	WILLIAM BEAUMONT HOSPITAL	3601 W. THIRTEEN MILE RD	ROYAL OAK	MI	48073	OAKLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/18/2019	NEW	$341,614
														Subtotal = $341,614

Grand Total All Awards = $1,668,891

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Developing therapeutic strategies to elicit metabolic synthetic lethality in glioblastoma

Award Number: R01NS110838

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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