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Metabolic and molecular regulation of myeloid cell functions in brain cancer

Award Number: R01NS131912
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: 04/15/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Metabolic and molecular regulation of myeloid cell functions in brain cancer - Glioblastoma (GBM), the most aggressive and lethal form of brain cancer, is characterized by a profound immunosuppressive microenvironment (TME) that restricts the effects of promising immunotherapies. Therefore, there is a pressing need to develop more effective interventions to overcome this mechanism of resistance. Tumor associated macrophages (TAMs) are a mixture of monocyte-derived macrophages (MDM) and microglia (MG), and they are instrumental for the maintenance of the immunosuppressive state of GBM. However, there are no effective approaches to overcome the immunosuppressive activity of TAMs in GBM, mainly due to an incomplete understanding of TAM regulatory functions. Our long term-goal is to dissect targetable metabolic and molecular mechanisms regulating TAM functions in the context of GBM; as these discoveries will facilitate novel therapies to target immunosuppression and improve the dismaying outcome of GBM patients. A recent study demonstrated that TAM are major consumers of glucose and maintain a robust glucose metabolism in the TME. However, it has not yet been determined how GBM supports the adaptation to glucose metabolism in TAMs and the functional consequences of this adaptation also remain elusive. Endoplasmic reticulum (ER) stress activation is associated with the malignant progression of glioma and with the infiltration of anti-inflammatory macrophages. PKR-like ER kinase (PERK), a critical ER stress sensor, was found to be significantly activated in human glioma tissues, and its inhibition altered ATP/lactate production by glioma cells. Our preliminary data expanded these findings indicating that MDM demonstrated highest glucose avidity among MG and neoplastic cells in GBM tumors, and PERK was strongly activated in GBM infiltrating GLUT1+MDM. Contrary to MG, MDM exhibited potent immunosuppressive activity. GLUT1+MDM were the only contributors to the suppressive activity associated with MDM in GBM tumors. GBM-derived factors primed activation of PERK signaling in MDM, which correlated with metabolic reprogramming resulting in high glycolysis, immunosuppressive functions, histone lactylation, and no change in histone acetylation. Based on our crucial observations, we hypothesize that a PERK-driven perturbation of glucose metabolism in MDM governs their immunosuppressive functions via lactate-derived lactylation of histone lysine residues. We will test this hypothesis through the following aims: Aim1: to elucidate underlying mechanisms of how PERK governs glycolysis in MDM in GBM tumors; Aim2: to define glucose-driven epigenetic modifications that regulates immunosuppressive programs in MDM; Aim3: to investigate the therapeutic potential of an epigenetic targeting approach to modulate the functions of TAMs in GBM. The proposed studies are highly innovative because they will elucidate a previously uncharacterized link between ER stress and glucose metabolism that regulates the activity of TAMs via epigenetic mechanisms. Our proposal will provide a mechanistic rationale for the development of novel therapies to target immunosuppressive TAMs and enhance the efficacy of immunotherapy in GBM patients.


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 = $473,753 )
2025	2025	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	3/27/2025	NON-COMPETING CONTINUATION	$426,379
2025	2025	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	3	8/5/2025	NON-COMPETING CONTINUATION	$47,374
2025	2024	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	2/20/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$38,505
2025	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/20/2025	NEW	-$38,505
														Subtotal = $473,753

Issue Date FY: 2024 ( Subtotal = $233,071 )
2024	2024	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	9/17/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$486,185
2024	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/16/2024	NEW	-$253,114
														Subtotal = $233,071

Issue Date FY: 2023 ( Subtotal = $464,399 )
2023	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/14/2023	NEW	$464,399
2023	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	7/18/2023	NEW	$0
														Subtotal = $464,399

Grand Total All Awards = $1,171,223

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Metabolic and molecular regulation of myeloid cell functions in brain cancer

Award Number: R01NS131912

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: 04/15/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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