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Drivers of metabolic plasticity promote radiation resistance in glioblastoma multiforme

Award Number: R01CA251872
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/06/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Drivers of metabolic plasticity promote radiation resistance in glioblastoma multiforme - ABSTRACT Radiation therapy (RT) is a very effective treatment modality for improving local control and overall survival for many cancer types. However, glioblastoma multiforme (GBM) displays remarkable radioresistance. Although, post-surgical RT (total dose of 60Gy in 2Gy fractions) is the only treatment modality that increases overall survival for GBM patients, GBM universally recurs and is fatal. Resistance to RT is therefore a major contributor to treatment failure. Overcoming radiation resistance of these tumors is one of the major remaining frontiers in Radiation Oncology that, if resolved, could dramatically improve outcomes in this disease. Amongst the many contributing factors that have been proposed, GBM metabolism and its role in generating resistance to oxidative stress, such as during RT is a promising therapeutic angle that we will exploit in this proposal. Specifically, we have evidence that irradiated GBM cells reprogram their metabolism towards antioxidant pathways, by funneling glucose through the NADPH- generating pentose phosphate pathway (PPP). Such metabolic reprogramming during RT is mediated in part by the glycolytic enzyme PKM2 and in part by the transcription factor NRF2. Oxidative stress-dependent inactivation of PKM2 or activation of NRF2, both result in rerouting of glycolytic intermediates into the PPP. In addition, we have evidence that PKM2 is a NRF2 target. Therefore, we hypothesize that PKM2 and NRF2 cooperate in driving an antioxidant metabolic response in irradiated GBM cells that promotes resistance to RT. Of importance is the fact that PKM2 is overexpressed in GBM tumors, while normal brain tissue only expresses PKM1. Also, small molecule activators of PKM2 are available that exacerbate oxidative stress and have anti-tumor activity, although they have not been tested in GBM or with RT. These activators cross the blood brain barrier making them suitable for combining with RT to sensitize GBM tumors. Therefore, it is also proposed that interfering with the NRF2-PKM2-metabolism axis would limit the antioxidant, pro-survival metabolic reprogramming induced by radiation and improve the effect of RT in human and mouse models of 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: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	5	6/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $672,458 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	001	5	6/19/2024	SUPPLEMENT FOR EXPANSION	$333,450
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	5	6/11/2024	NON-COMPETING CONTINUATION	$339,008
														Subtotal = $672,458

Issue Date FY: 2023 ( Subtotal = $700,713 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	002	4	9/13/2023	SUPPLEMENT FOR EXPANSION	$7,020
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	001	4	7/17/2023	SUPPLEMENT FOR EXPANSION	$343,980
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	4	6/27/2023	NON-COMPETING CONTINUATION	$349,713
														Subtotal = $700,713

Issue Date FY: 2022 ( Subtotal = $680,607 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	001	3	7/15/2022	SUPPLEMENT FOR EXPANSION	$330,894
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	3	6/14/2022	NON-COMPETING CONTINUATION	$349,713
														Subtotal = $680,607

Issue Date FY: 2021 ( Subtotal = $356,850 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	2	6/7/2021	NON-COMPETING CONTINUATION	$356,850
														Subtotal = $356,850

Issue Date FY: 2020 ( Subtotal = $356,850 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Treatment Research	000	1	7/6/2020	NEW	$356,850
														Subtotal = $356,850

Grand Total All Awards = $2,767,478

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Drivers of metabolic plasticity promote radiation resistance in glioblastoma multiforme

Award Number: R01CA251872

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/06/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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