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Defining cellular states of quiescence in human brain tumors

Award Number: R01NS119650
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: 02/15/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Defining cellular states of quiescence in human brain tumors - PROJECT SUMMARY The most aggressive type of brain tumor, grade IV glioma known as glioblastoma (GBM), is one of the few tumor types with both a poor outcome and minimal improvement in survival in the past decades. For GBM, like other solid cancers, intratumoral heterogeneity is likely an important factor in mediating therapeutic response. In particular, quiescent, G0-like subpopulations may engender tumors with more robust responses to treatment regimens and allow for tumor regrowth after standard of care (SOC). However, G0-like tumor populations are currently ill-defined, even after application of single cell genomics to GBM. Our failure to fully comprehend and experimentally model quiescent/G0-like states represents a critical knowledge gap, but also a key opportunity, for glioma and other cancers, as neutralizing G0 cells could effectively prevent chemoradiotherapy resistance and tumor recurrence. The purpose of this grant is to provide a functional and molecular definition of G0-like states in GBM tumors and their responses to SOC. In Aim 1, we will define molecular networks governing long- and short-term quiescent states in GBM patient tumors using a novel G0 reporter system in combination with single cell genomic analysis. In Aim 2, we will test the hypothesis that dormant G0 GBM cells have unique RNA and chromatin signatures required for SOC survival and tumor regrowth. In Aim 3, we will study and nominate the NuA4/KAT5 lysine acetyltransferase complex as a key regulator of G0-like states in GBM and candidate therapeutic target. The Aims are built on strong preliminary data, including: the creation of a machine learning-based method for identifying G0-like cells in gliomas, integrated analysis of single cell RNA and chromatin analysis of primary and PDX GBM tumors with standard of care, a functional genomic screen to identify regulators of GBM G0, and key experimental models to functionally dissect G0 states in GBM tumor models. If successful, this grant will produce a new working model for GBM G0-like states, provide key genes and gene networks associated with G0, and analysis tools for identifying G0-like states in clinical samples. It will also define how these populations respond to SOC and shift tumor dynamics during recurrence. Finally, it will provide data for a new therapeutic strategy, downgrading , where grade IV tumors are made less aggressive by triggering extended or permanent G0-like states in tumor cells.


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 = $463,899 )
2025	2025	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	12/17/2024	NON-COMPETING CONTINUATION	$463,899
														Subtotal = $463,899

Issue Date FY: 2024 ( Subtotal = $499,981 )
2024	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/29/2023	NON-COMPETING CONTINUATION	$463,899
2024	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	4/23/2024	NON-COMPETING CONTINUATION	$36,082
														Subtotal = $499,981

Issue Date FY: 2023 ( Subtotal = $515,443 )
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	1/6/2023	NON-COMPETING CONTINUATION	$463,899
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	4	1/31/2023	NON-COMPETING CONTINUATION	$51,544
2023	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	11/16/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$82,644
2023	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/16/2022	NON-COMPETING CONTINUATION	-$82,644
														Subtotal = $515,443

Issue Date FY: 2022 ( Subtotal = $518,058 )
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	8/10/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$282,498
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	6/13/2022	NON-COMPETING CONTINUATION	-$282,498
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	3	9/1/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$51,806
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/22/2021	NON-COMPETING CONTINUATION	$466,252
														Subtotal = $518,058

Issue Date FY: 2021 ( Subtotal = $553,130 )
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/11/2021	NEW	$553,130
														Subtotal = $553,130

Grand Total All Awards = $2,550,511

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Defining cellular states of quiescence in human brain tumors

Award Number: R01NS119650

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: 02/15/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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