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Ornithine Aminotransferase Inactivation, a New Approach for Treatment of Cancers

Award Number: R01CA260250
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Ornithine Aminotransferase Inactivation, a New Approach for Treatment of Cancers - Project Summary/Abstract Recently, it was found that the enzyme ornithine aminotransferase (OAT) is overexpressed in hepatocellular carcinoma (HCC), the most common primary malignancy of the liver and the 2nd leading cause of cancer-related death in men (6th in women) worldwide. There are relatively few molecules known to inhibit the activity of OAT, and those that have been reported focus on their ability to increase the concentration of ornithine as a potential treatment for acute ammonia intoxications and hepatogenic encephalopathy. The objective of this proposal is to use computer modeling, based on the known crystal structures of human OAT and other PLP-dependent enzymes with our previously-active inactivators bound, to assist in the design of new inactivators of OAT that are selective against other related enzymes to lower the potential of side effects from off-target inhibition. Modifications to our earlier compounds will be made to improve on potency and pharmacokinetic properties. The mechanisms of those compounds that selectively inactivate OAT will be investigated. X-ray crystal structures of the inactivators bound to OAT will be obtained by our collaborator, Dr. Dali Liu, to assist in further structural modifications. Compounds that are potent and selective inactivators of OAT will be tested by Dr. Wenan Qiang against several cancer cell lines also found to overexpress OAT and carry out PDX studies with the most effective compounds. He also will corroborate that the compounds inhibit secretion of alpha-fetoprotein, a biomarker for HCC, and that OAT is the target. The goal is to identify one or more compounds that are selective inhibitors/inactivators of OAT that suppress the growth of HCC, and other cancers that overexpress OAT, in animals. These compounds would be first-in-class treatments for HCC, a cancer that is highly resistant to both standard cancer chemotherapy and radiation therapy, and the prognosis for recovery is very poor, as well as other OAT-expressing cancers.


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 = $373,062 )
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	001	5	7/8/2025	NON-COMPETING CONTINUATION	$37,307
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	000	5	3/17/2025	NON-COMPETING CONTINUATION	$335,755
														Subtotal = $373,062

Issue Date FY: 2024 ( Subtotal = $355,543 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	000	4	3/5/2024	NON-COMPETING CONTINUATION	$336,831
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$18,712
														Subtotal = $355,543

Issue Date FY: 2023 ( Subtotal = $360,196 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	000	3	3/28/2023	NON-COMPETING CONTINUATION	$360,196
														Subtotal = $360,196

Issue Date FY: 2022 ( Subtotal = $358,047 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	000	2	4/27/2022	NON-COMPETING CONTINUATION	$358,047
														Subtotal = $358,047

Issue Date FY: 2021 ( Subtotal = $412,090 )
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Cancer Treatment Research	000	1	4/9/2021	NEW	$412,090
														Subtotal = $412,090

Grand Total All Awards = $1,858,938

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Ornithine Aminotransferase Inactivation, a New Approach for Treatment of Cancers

Award Number: R01CA260250

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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