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The role of glutaminolysis as a therapeutic target in T-ALL

Award Number: R01CA236936
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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The role of glutaminolysis as a therapeutic target in T-ALL - ABSTRACT A key hallmark of human cancer is cancer-specific metabolic rewiring. Notably, this area of research has gained renewed attention in the last decade after several studies demonstrated that key oncogenes in human cancer, such as AKT, KRas, MYC or NOTCH1, have differential and specific effects on primary cellular metabolism, leading to the hypothesis that selective targeting of those routes might be an attractive therapeutic approach. In this context, I recently identified glutaminolysis as a critical pathway in NOTCH1-driven T-lineage acute lymphoblastic leukemia (T-ALL), a hematological malignancy where relapses occur in up to 20% of pediatric and 50% of adult patients, who ultimately succumb to refractory disease. Importantly, inhibition of glutaminolysis genetically, via deletion of glutaminase (Gls), or pharmacologically, using Gls inhibitors, results in anti-leukemic effects and is highly synergistic with anti-NOTCH1 therapies. Notably, Gls selective inhibitors are currently being explored in clinical trials for hematological malignancies, and glutaminolysis has also been proposed as a therapeutic target in a variety of solid tumors. However, the role of glutamine in vivo is still not well understood and Gls-deficient T-ALLs eventually progress, underscoring the need to understand the mechanisms of relapse. My preliminary data suggests that glutamine-derived carbon might feed into the TCA cycle and Gls- deficient T-ALLs might still use glutamine even in the absence of glutaminase. Moreover, my preliminary data points to a role of glutaminase in stemness. Therefore, this research proposal seeks to: 1) dissect the role of glutaminase in T-ALL in vivo and unravel the mechanisms of escape to Gls loss;; 2) address the role of glutaminolysis in stemness;; and 3) identify synthetic lethal pathways/genes with pharmacological inhibition of glutaminase or with genetic loss of glutaminase using CRIPSR/Cas9 screens in vitro and experimental therapeutic experiments in vivo. These studies will reveal as yet undiscovered fundamental mechanisms implicated in the metabolic and epigenetic rewiring of T-ALL, will advance our understanding of the role of Gls and glutaminolysis in cancer, and will help us rationally design combinations of metabolic or epigenetic targeted therapies that will result in stronger therapeutic effects with decreased chances of relapse.


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: 2024 ( Subtotal = $0 )
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cancer Biology Research	001	5	3/21/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$168,508
2024	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Biology Research	000	4	3/21/2024	NON-COMPETING CONTINUATION	-$168,508
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $356,438 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cancer Biology Research	001	5	7/21/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$356,438
2023	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	000	4	7/11/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $356,438

Issue Date FY: 2022 ( Subtotal = $363,713 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	000	4	7/11/2022	NON-COMPETING CONTINUATION	$363,713
														Subtotal = $363,713

Issue Date FY: 2021 ( Subtotal = $363,713 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	000	3	5/26/2021	NON-COMPETING CONTINUATION	$363,713
														Subtotal = $363,713

Issue Date FY: 2020 ( Subtotal = $363,713 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	000	2	6/18/2020	NON-COMPETING CONTINUATION	$363,713
														Subtotal = $363,713

Issue Date FY: 2019 ( Subtotal = $336,720 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	000	1	6/17/2019	NEW	$336,720
														Subtotal = $336,720

Grand Total All Awards = $1,784,297

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The role of glutaminolysis as a therapeutic target in T-ALL

Award Number: R01CA236936

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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