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Exploiting cell fate transition to overcome radiation resistance in glioblastoma

Award Number: R01CA282756
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/28/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Exploiting cell fate transition to overcome radiation resistance in glioblastoma - PROJECT SUMMARY Glioblastoma (GBM) is a devastating brain tumor that affects about 15,000 Americans every year. Despite maximal surgical resection and chemoradiation, GBMs remain incurable. GBMs are notoriously radiation resistant. Molecular subtyping of GBMs by genomic analyses of patient tumors identified three major subtypes, termed Proneural (PN), Classical or Mesenchymal (MES), based on gene expression patterns. Collaborative efforts between the Sulman and Bhat laboratories over the years has uncovered glioma stem-like cells (GSCs) closely resembling molecular subtypes of GBM. These states, however, exhibit plasticity and we pioneered the notion of PN to MES transition based on studies using patient derived GSCs linking MES signatures with radio- resistance and identifying master transcription factors associated with the MES subtype. New exciting preliminary data from our laboratories have identified three independent molecular targets associated with radiation resistance. Using whole-genome CRISPR screens to identify gene targets associated with enhanced radiation sensitivity as well as and mass spectrometric evaluation of radiation induced protein complexes, we have uncovered three players involved in metabolic, epigenetic and DNA repair pathways that can be targeted to overcome radiation resistance in GSCs. The overall goal of this proposal is to combine these druggable targets with the standard use of fractionated photon radiation therapy (RT) and convert GSCs from radioresistant to radiosensitive. In Aim 1, we will examine if inhibition of N-acylneuraminate-9-phosphatase (NANP) will lead to radiosensitization of GBM transitioning from MES to PN states via metabolic reprogramming. In Aim 2, we will test if targeting High Mobility Group Box-2 (HMGB2) leads to a block of MES transitioning and alterations of chromatin and if it is lethal in combination with radiation. Finally, in Aim 3, we will examine the radiosensitizing effects of neuronal differentiation with combined TAZ inhibitors and ionizing radiation in pre-clinical models of GBM. Our proposal is significant because this is the first comprehensive study to examine the radiosensitizing effects of cell state transition blockade in GBM. Data generated from this grant will encompass TCGA datasets, patient derived GSCs, clinically relevant xenograft models as well as testing of inhibitors in these models with a trajectory toward Phase I clinical trials to overcome radioresistance in patients with GBM.


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: 2027 ( Subtotal = $0 )
2027	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	000	3	10/8/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	000	3	9/4/2026	NON-COMPETING CONTINUATION	-$627,652
2026	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Treatment Research	001	4	9/4/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$627,652
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $676,623 )
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	000	3	6/12/2025	NON-COMPETING CONTINUATION	$676,623
														Subtotal = $676,623

Issue Date FY: 2024 ( Subtotal = $652,198 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	000	2	6/24/2024	NON-COMPETING CONTINUATION	$652,198
														Subtotal = $652,198

Issue Date FY: 2023 ( Subtotal = $709,593 )
2023	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	000	1	7/28/2023	NEW	$709,593
														Subtotal = $709,593

Grand Total All Awards = $2,038,414

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Exploiting cell fate transition to overcome radiation resistance in glioblastoma

Award Number: R01CA282756

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/28/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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