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Targeting Glioblastoma Stem Cells

Award Number: R35CA283998
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2031

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Targeting Glioblastoma Stem Cells - PROJECT SUMMARY/ABSTRACT Glioblastoma represents one of the most lethal types of cancers. Despite extensive molecular characterization, precision medicine efforts have largely failed for glioblastoma therapy, suggesting that these complex tumors are resilient ecosystems that overcome singular therapeutic approaches. Aging is strongly associated with increased incidence and mortality of most cancers, including glioblastoma. However, the cellular and molecular mechanisms by which aging promotes tumor initiation and progression remain poorly understood. Tissue-specific stem cells contribute to development, renewal, and regeneration of most organs. Neural stem cells (NSCs) undergo little to no cell division during normal homeostasis but become activated by tissue injury with wound responses. NSCs reside in specialized niches that provide maintenance cues and regulate the balance between quiescence and proliferation. Inflammation and nutrient constraints in NSC niches in the aging brain promotes quiescence and decreased regenerative potential. Like the normal brain, glioblastomas contain cellular hierarchies with stem-like tumor cells at the apex. While controversial, these cancer stem cells contribute to therapeutic resistance, invasion into normal brain, generation of new vasculature, and evasion of anti-tumor immunity. Cancer stem cells display remarkable plasticity, rendering therapeutic targeting strategies challenging. In the proposed studies, the Rich laboratory will leverage insights from aging in the nervous system and the molecular circuitry of cancer stem cells to understand how aging promotes tumor growth through cell autonomous mechanisms and interactions with the microenvironment. We will leverage preliminary observations that cancer stem cells reprogram essential metabolic pathways through integration of extrinsic signals from tumor-infiltrating immune cells and vasculature to promote epigenetic reprogramming, empowering sustained proliferation, self-renewal, and immune evasion. Based on this background, we hypothesize that aging promotes reprogramming of the tumor immune microenvironment and cell autonomous nuclear structural regulation that will inform the development of novel brain tumor treatments. Using spatial transcriptomics and metabolomics of patient tumors and organoids, we will investigate the metabolic alterations within the aging tumor microenvironment to derive multi-modal therapies that disrupt the dynamic growth and survival mechanisms within tumors.


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: 2026 ( Subtotal = $824,516 )
2026	2026	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Biology Research	000	3	12/10/2025	NON-COMPETING CONTINUATION	$824,516
														Subtotal = $824,516

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Biology Research	001	2	7/31/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$722,890
2025	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Biology Research	002	1	8/12/2025	NEW	$0
2025	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Biology Research	000	1	7/31/2025	NEW	-$722,890
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $954,000 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Biology Research	000	1	8/23/2024	NEW	$954,000
														Subtotal = $954,000

Grand Total All Awards = $1,778,516

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Targeting Glioblastoma Stem Cells

Award Number: R35CA283998

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2031

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