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Gene-tobacco carcinogen interactions and lung cancer risk - a novel approach for precision cancer prevention

Award Number: R01CA269223
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/16/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Gene-tobacco carcinogen interactions and lung cancer risk - a novel approach for precision cancer prevention - The tobacco-specific nitrosamine (TSNA), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is considered a major contributor to the induction of lung cancer in smokers. The metabolism of NNK is complex with its carcinogenic effects likely via the formation of its major pro-carcinogenic metabolite, 4-(methylnitrosamino)-1- (3-pyridyl)-1-butanol (NNAL). Two enantiomers of NNAL are formed: (R)- and (S)-NNAL, both of which are extensively detoxified by glucuronidation in humans. Our novel preliminary data demonstrate a strong and statistically significant inverse association between the ratio of urinary (R)-NNAL-glucuronide (Gluc)/(S)-NNAL- Gluc and lung cancer risk in two independent prospective cohort studies. Furthermore, smokers homozygous for the deletion polymorphism of the major NNAL-glucuronidating enzyme, UGT2B17, had a significant 3-fold higher risk for lung cancer than those with at least one functional UGT2B17 allele in both cohorts. These data strongly support our hypothesis that (R)-NNAL plays a key role in tobacco-induced lung carcinogenesis and suggests that we have identified novel important phenotypic and genetic markers of lung cancer risk. The goal of this proposal is to evaluate the importance of NNAL enantiomers and glucuronides in lung cancer carcinogenesis, and to elucidate novel phenotypic and genetic markers of NNAL formation and elimination pathways and lung cancer risk in multiple populations. Our goals are to prospectively evaluate whether the levels or ratios of specific urinary NNAL isomers or glucuronides are associated with lung cancer risk in: (1) Chinese smokers from three cohort studies from Shanghai and Singapore, and (2) White and Black smokers from the Southern Community Cohort Study, and to subsequently screen and validate genetic variants associated with the variability in NNAL enantiomer and glucuronide formation. These studies should provide crucial insight for understanding variability and establishing phenotypes and genotypes important in lung cancer risk and will assist in identifying smokers at high risk for lung cancer for the development of chemopreventive strategies targeting the NNK metabolism pathway.


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 = $615,223 )
2025	2025	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Cancer Cause and Prevention Research	001	3	4/4/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$615,223
2025	2025	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Cancer Cause and Prevention Research	003	3	5/12/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$197,745
2025	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Cause and Prevention Research	002	2	5/12/2025	NON-COMPETING CONTINUATION	-$197,745
2025	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Cause and Prevention Research	000	2	4/4/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $615,223

Issue Date FY: 2024 ( Subtotal = $605,270 )
2024	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Cause and Prevention Research	001	2	4/25/2024	NON-COMPETING CONTINUATION	$31,854
2024	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Cause and Prevention Research	000	2	11/7/2023	NON-COMPETING CONTINUATION	$573,416
														Subtotal = $605,270

Issue Date FY: 2023 ( Subtotal = $668,019 )
2023	2023	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Cancer Cause and Prevention Research	000	1	12/19/2022	NEW	$668,019
														Subtotal = $668,019

Grand Total All Awards = $1,888,512

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Gene-tobacco carcinogen interactions and lung cancer risk - a novel approach for precision cancer prevention

Award Number: R01CA269223

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/16/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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