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Characterizing vitamin B6 pathway dependency in acute myeloid leukemia

Award Number: R37CA276938
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/05/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Characterizing vitamin B6 pathway dependency in acute myeloid leukemia - PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is one of the most devastating blood cancers, and it affects around one million people and results in 147,000 deaths per year worldwide. AML is characterized by the abnormal production of myeloid lineage of blood cells and the rapid growth of leukemia blasts in bone marrow and peripheral blood. AML is a very aggressive cancer, and it progresses rapidly and AML patients become fatal within weeks to months. Currently, therapeutic options for AML are very limited. Only about 35% of AML patients under 60 years-old and 10% over 60 years-old benefit from standard chemotherapy. Thus, there is an urgent and unmet medical need to develop new therapeutic approaches particularly combination therapies with advanced efficacy and reduced toxicity for AML patients. Our long-term goals of the proposed research are to study abnormal vitamin pathways as metabolic dependencies in AML, to investigate critical regulators of vitamin pathways in supporting AML cell aberrant proliferation, and to identify druggable therapeutic targets in AML. We have recently uncovered vitamin B6 pathway as a novel dependency in AML. Based on this finding, we hypothesize that vitamin B6 pathway is a specific anti-leukemia target and has promising therapeutic potential to treat AML. To assess the hypothesis, we have identified multiple key enzymes in vitamin B6 dependent metabolic pathways essential for AML cell, but not for normal bone marrow hematopoietic stem and progenitor cell and immune cell, proliferation. Depletion of these key enzymes exhibited robust inhibition on AML proliferation. We have also validated vitamin B6 pathway as a pharmacologically actionable pathway and showed that vitamin B6 pathway inhibitors exhibit promising therapeutic efficacy in multiple genetically engineered AML models in vivo. These robust preliminary data encourage us to pursue three Specific Aims to further characterize vitamin B6 pathway: 1) to characterize both upstream and downstream regulators of vitamin B6 pathway in AML; 2) to evaluate the synergy between vitamin B6 pathway and BCL-2 in AML therapeutics to further enhance its efficacy; and 3) to perform functional genomics screens to identify vitamin B6 pathway synergistic effectors in AML. We propose to study AML from the aspect of vitamin B6 pathway and metabolic programming, a process which is novel and essential for AML cell proliferation. The proposed research will be focusing on both mechanistic understanding and therapeutic targeting of vitamin B6 pathway in association with different synergistic effectors in AML. The major goals of this proposal are to identify the unique vitamin B6 upstream regulators and downstream effectors as well as its synergistic effectors to treat AML. The proposal is significant because it will not only uncover the underlying mechanism but also pinpoint therapeutic targets to synergistically enhance the anti-leukemia effects in AML.


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 = $395,280 )
2026	2026	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPG HBR	NY	11724	SUFFOLK	USA	Cancer Biology Research	000	4	12/18/2025	NON-COMPETING CONTINUATION	$395,280
														Subtotal = $395,280

Issue Date FY: 2025 ( Subtotal = $439,200 )
2025	2025	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPG HBR	NY	11724	SUFFOLK	USA	Cancer Biology Research	000	3	1/9/2025	NON-COMPETING CONTINUATION	$395,280
2025	2025	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPG HBR	NY	11724	SUFFOLK	USA	Cancer Biology Research	001	3	9/19/2025	NON-COMPETING CONTINUATION	$43,920
														Subtotal = $439,200

Issue Date FY: 2024 ( Subtotal = $417,241 )
2024	2024	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPRING HARBOR	NY	11724	SUFFOLK	USA	Cancer Biology Research	000	2	12/19/2023	NON-COMPETING CONTINUATION	$395,280
2024	2024	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPG HBR	NY	11724	SUFFOLK	USA	Cancer Biology Research	001	2	4/18/2024	NON-COMPETING CONTINUATION	$21,961
														Subtotal = $417,241

Issue Date FY: 2023 ( Subtotal = $439,200 )
2023	2023	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPRING HARBOR	NY	11724	SUFFOLK	USA	Cancer Biology Research	000	1	1/5/2023	NEW	$439,200
2023	2023	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPRING HARBOR	NY	11724	SUFFOLK	USA	Cancer Biology Research	001	1	5/10/2023	NEW	$0
														Subtotal = $439,200

Grand Total All Awards = $1,690,921

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Characterizing vitamin B6 pathway dependency in acute myeloid leukemia

Award Number: R37CA276938

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/05/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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