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The role and mechanism of necrosis in glioblastoma

Award Number: R01NS119547
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: 02/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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The role and mechanism of necrosis in glioblastoma - Project Summary Gliomas are major primary brain tumors, of which glioblastomas (GBM) are the most common and aggressive forms. The poor outcome of traditional treatment for these tumors demands targeted therapies based on identified mechanisms that drive tumor development. Molecular pathology has classified GBM into subtypes, among which the mesenchymal (MES) group is the most malignant. It is still unclear how GBM MES differentiation is achieved. Recent anatomically based transcriptome studies found that tumor cells associated with the necrotic region have higher expression of the MES signature genes, suggesting that the necrotic tumor microenvironment may contribute to MES differentiation and could be exploited as a therapeutic target. The goal of this project is to mechanistically and functionally study GBM necrosis, and identify vulnerabilities of GBM MES progression for therapeutics. We have established the follow premise for the proposed studies. First, we have developed novel pathologically relevant GBM mouse models showing MES differentiation and extensive necrosis. Second, we identified ferroptosis as a novel mechanism for GBM necrosis. Third, in both patient GBM samples and mouse models, we found that the necrotic tumor areas are infiltrated by neutrophils. Our studies suggested that these tumor-associated neutrophils (TANs) are necessary and sufficient to induce tumor cell ferroptosis. Furthermore, we found that ferroptosis and TANs are associated with the hypoxic tumor microenvironment. We hypothesize that GBM necrosis occurs through neutrophil-triggered ferroptosis, and this process is orchestrated by the hypoxic tumor microenvironment. We further hypothesize that ferroptosis could promote tumor progression and be targeted for therapeutic purposes. We propose the following three specific aims: 1) to determine the mechanism of tumor cell ferroptosis induced by TANs; 2) to determine the role of hypoxic tumor microenvironment in tumor cell ferroptosis; 3) to demonstrate the role of ferroptosis in GBM progression and evaluate therapeutic effects of ferroptosis blockade. We will employ a panel of established human GBM cell lines, newly isolated human GBM cells, and mouse GBM models. GBM necrosis is a diagnostic hallmark, predicts tumor aggressiveness, and has deleterious effects on treatments. The nature and mechanism of cell death associated with this necrosis remain obscure. In addition, whether tumor necrosis blockade could benefit therapies is still unknown. By establishing the GBM models faithfully recapitulating the extent of necrosis observed in GBM patients and identification of ferroptosis as the underlying mechanism of tumor necrosis, this proposal will reveal vulnerabilities of GBM MES progression, which could be a novel avenue for GBM therapeutics.


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 = $354,108 )
2025	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/26/2025	NON-COMPETING CONTINUATION	$354,108
														Subtotal = $354,108

Issue Date FY: 2024 ( Subtotal = $381,650 )
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/25/2024	NON-COMPETING CONTINUATION	$27,542
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/31/2024	NON-COMPETING CONTINUATION	$354,108
														Subtotal = $381,650

Issue Date FY: 2023 ( Subtotal = $393,454 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/6/2023	NON-COMPETING CONTINUATION	$393,454
														Subtotal = $393,454

Issue Date FY: 2022 ( Subtotal = $393,454 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	5/3/2022	NON-COMPETING CONTINUATION	$39,346
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/21/2022	NON-COMPETING CONTINUATION	$354,108
														Subtotal = $393,454

Issue Date FY: 2021 ( Subtotal = $393,454 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/20/2021	NEW	$393,454
														Subtotal = $393,454

Grand Total All Awards = $1,916,120

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The role and mechanism of necrosis in glioblastoma

Award Number: R01NS119547

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: 02/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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