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Investigating the therapeutic potential of a novel glutamine antagonist in KEAP1 mutant lung cancer

Award Number: R01CA262562
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/19/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Investigating the therapeutic potential of a novel glutamine antagonist in KEAP1 mutant lung cancer - PROJECT SUMMARY/ABSTRACT Treating KRAS mutant lung adenocarcinoma (LUAD) remains a major challenge for clinical oncology. Approximately 20% of KRAS mutant LUAD tumors carry loss-of-function mutations in KEAP1, a negative regulator of NRF2, which is the master transcriptional regulator of the endogenous antioxidant response. Using CRISPR/Cas9-based somatic editing in a genetically engineered mouse model of KRAS-driven LUAD we demonstrated that loss of Keap1 hyper-activates Nrf2 and dramatically accelerates KRAS-driven LUAD. Combining CRISPR/Cas9-based genetic screening and metabolic analyses, we showed that Keap1 mutant cells are dependent on increased glutamine metabolism, and this property can be therapeutically exploited through the pharmacological inhibition. In this application we focus on characterizing the molecular mechanisms and therapeutic potential of targeting glutamine metabolism in KRAS-driven KEAP1 mutant LUAD This application aims to: 1) Assess the therapeutic potential of novel glutamine antagonist in both human and murine KRASG12D- and KRASG12C-driven KEAP1 mutant LUAD pre-clinical models, 2) Provide a rationale for sub-stratification of human lung cancer patients with KRAS-KEAP1 or -NRF2 mutant tumors as likely responders to glutamine antagonists and determine the therapeutic potential of combining with clinically relevant KC-Is with DRP-104. 3) Characterize the metabolic mechanisms underlying glutamine antagonist sensitivity in KRAS-driven KEAP1 mutant LUAD, and 4) Identify mechanisms of resistance to glutamine dependence. Our studies will provide a rationale for sub-stratification of patients with hyperactivation of the NRF2 pathway as treatment responders to DRP-104, a novel glutamine antagonist in clinical trials, which is pertinent to the goals of precision medicine.


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 = $589,932 )
2026	2026	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	000	3	12/19/2025	NON-COMPETING CONTINUATION	$589,932
														Subtotal = $589,932

Issue Date FY: 2025 ( Subtotal = $655,478 )
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	001	2	6/2/2025	NON-COMPETING CONTINUATION	$65,546
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	000	2	11/15/2024	NON-COMPETING CONTINUATION	$589,932
														Subtotal = $655,478

Issue Date FY: 2024 ( Subtotal = $672,853 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Treatment Research	000	1	12/19/2023	NEW	$672,853
														Subtotal = $672,853

Grand Total All Awards = $1,918,263

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Investigating the therapeutic potential of a novel glutamine antagonist in KEAP1 mutant lung cancer

Award Number: R01CA262562

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/19/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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