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Investigating the Proline Cycle as a Potential Cancer Therapy Target

Award Number: R01GM132640
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Investigating the Proline Cycle as a Potential Cancer Therapy Target - PROJECT SUMMARY Proline dehydrogenase (PRODH) and Δ1-pyrroline-5-carboxylate (P5C) reductase (PYCR) form a metabolic relationship known as the “proline cycle”, a novel pathway that impacts cellular growth and death pathways. The proline cycle is central to the metabolic shift that enables tumorigenesis and supports the metastatic cascade of cancer cells. PRODH is upregulated in metastasizing breast cancer cells, and PYCR1 is one of the most consistently upregulated enzymes across multiple cancer cell types. Thus, proline cycle enzymes have been proposed as potential cancer drug targets. A major goal of this project is to gain insight into whether these enzymes have binding sites that can be exploited for small molecule binding and establish target tractability, i.e., the likelihood of identifying modulators that interact effectively with these targets. Initial results are encouraging, as the chemical probes developed in the first phase of this project show activity in cellular and animal models of cancer. These results motivate our proposal to (1) develop new and more potent reversible inhibitors of PRODH and PYCR1, (2) explore the mechanism-based covalent inactivation of PRODH, and (3) define the mechanistic roles of the proline cycle using chemical probes in cancer cells. With these studies we will mechanistically dissect the role of proline metabolism in cancer progression. We expect this knowledge will in the long-term aid the development of new therapeutic strategies against cancer.


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 = $405,353 )
2025	2025	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Biomedical Research and Research Training	000	4	7/23/2025	NON-COMPETING CONTINUATION	$405,353
														Subtotal = $405,353

Issue Date FY: 2024 ( Subtotal = $419,478 )
2024	2024	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Biomedical Research and Research Training	001	3	9/10/2024	COMPETING CONTINUATION	$419,478
2024	2021	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Biomedical Research and Research Training	000	2	1/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $419,478

Issue Date FY: 2021 ( Subtotal = $349,563 )
2021	2021	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Biomedical Research and Research Training	000	2	8/11/2021	NON-COMPETING CONTINUATION	$349,563
														Subtotal = $349,563

Issue Date FY: 2020 ( Subtotal = $368,805 )
2020	2020	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Biomedical Research and Research Training	000	1	9/4/2020	NEW	$368,805
														Subtotal = $368,805

Grand Total All Awards = $1,543,199

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Investigating the Proline Cycle as a Potential Cancer Therapy Target

Award Number: R01GM132640

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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