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Regulation of esophageal tumorigenesis by protein adduction

Award Number: R03CA286671
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Regulation of esophageal tumorigenesis by protein adduction - SUMMARY Esophageal adenocarcinoma (EAC) is the most prevalent histological type of esophageal malignancy in the US and many Western nations. This tumor remains deadly as approximately 80% of patients are diagnosed at advanced stages and have a low five-year survival rate. Gastroesophageal reflux disease (GERD) is one of the strongest risk factors for EAC. In GERD patients, the epithelial lining of the esophagus is exposed to the gastroesophageal reflux (GER) that contains gastric acid frequently mixed with duodenal bile. The esophageal epithelial cells undergoes severe damage from exposure to acid and bile salts. This exposure also promotes inflammation, which can exacerbate tissue damage and lead to the development of Barrett's esophagus (BE). BE is a preneoplastic condition that is disposed to malignant transformation. The molecular mechanisms of esophageal tumorigenesis in conditions of esophageal reflux injury remain poorly understood. We have developed an innovative hypothesis to investigate how isolevuglandin (isoLG) lipid derivatives that adduct multiple proteins in conditions of esophageal reflux facilitate tumorigenic processes by protein adduction. IsoLGs are formed from the free radicals induced peroxidation of lipids and cyclooxygenase (COX) and are highly reactive for lysine as well as other cellular amines. IsoLGs bind covalently with the protein molecules to inflict damage before being recognized by cellular defense mechanisms. In our experimental conditions of esophageal reflux, p63 is found to be one of the most adducted proteins by isoLGs. P63 is a master regulator of esophageal epithelial development, which also regulate a broad spectrum of genes involved in different cellular processes such as DNA repair, stemness, proliferation and differentiation. Our preliminary data strongly support the hypothesis by providing evidence of the alteration of p63 protein by adduction. In aim 1, using in vitro cell systems, this proposal will examine the unique mechanisms regulating p63 signaling pathway by protein adduction and its biological impact in conditions of esophageal reflux injury. In aim 2, we will study the p63 protein adduction in in vivo mice model and test various pharmacological options to reverse this process. If successful, this study will provide a new therapeutic approach to prevent the pro-tumorigenic alterations of esophageal 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: 2026 ( Subtotal = $0 )
2026	2025	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cancer Biology Research	000	2	10/7/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $76,750 )
2025	2025	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cancer Biology Research	000	2	12/9/2024	NON-COMPETING CONTINUATION	$76,750
														Subtotal = $76,750

Issue Date FY: 2024 ( Subtotal = $76,750 )
2024	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cancer Biology Research	000	1	1/1/2024	NEW	$76,750
														Subtotal = $76,750

Grand Total All Awards = $153,500

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Regulation of esophageal tumorigenesis by protein adduction

Award Number: R03CA286671

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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