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Chemoprevention of lung cancer with the β-blocker carvedilol

Award Number: R03CA256241
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2024

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Chemoprevention of lung cancer with the β-blocker carvedilol - Abstract Lung cancer is the leading cause of cancer-related death for both men and women. Chronic exposure to carcinogens that are present in tobacco smoking or air pollution is a known factor causing lung cancer. Although the most important strategy to manage lung cancer is prevention, no effective chemopreventive agents currently exist. Carvedilol is an FDA-approved oral β-blocker for cardiovascular diseases with safety records for long term use. It displays cancer-preventive properties against chemical carcinogen-induced skin hyperplasia and ultraviolet-induced squamous carcinoma development in mice after oral or topical administration. However, as a very potent β-blocker, carvedilol may induce unwanted side effects due to high-level β-adrenergic receptors in the respiratory and cardiovascular system. Interestingly, the clinical form of carvedilol is racemic, consisting of equal amount of S- and R-carvedilol: although S-carvedilol is a β-blocker, R-carvedilol enantiomer does not exhibit β-blocker activity and did not affect blood pressure and heart rate in mice. Since our previous study suggests that carvedilol prevents skin cancer independently of β-blockade, we hypothesized that both the racemic carvedilol and R-carvedilol are able to prevent lung carcinogenesis induced by tobacco carcinogen. Supporting this hypothesis, our preliminary studies demonstrate that carvedilol, S- and R-carvedilol had similar protective activity against single dose benzo(a)pyrene-induced oxidative stress and inflammation in mice. In addition, carvedilol, S- and R-carvedilol similarly blocked EGF-induced malignant transformation of mouse epidermal cells and activation of the transcription factor ELK-1 which is a promoter of lung carcinogenesis. Therefore, in this application, we propose to evaluate the chemopreventive efficacy and mechanism for both carvedilol and R- carvedilol using in vitro and in vivo lung carcinogenesis models induced by the prototypical tobacco carcinogen benzo(a)pyrene. Aim 1 is to examine the effects of carvedilol and R-carvedilol in benzo(a)pyrene-induced transformation, DNA damage and oncogenic signaling in non-tumorous human bronchial epithelial cell cultures and to determine whether the cancer preventive activity is dependent on the β-adrenergic signaling. Aim 2 is to determine the chemopreventive efficacy of carvedilol and R-carvedilol in a mouse model of lung cancer induced by benzo(a)pyrene. Since carvedilol and R-carvedilol are FDA approved agents, the outcome from this project should be readily translated into a clinical lung cancer chemoprevention regimen. R-carvedilol, lacking β- blocking activity, is expected with improved therapeutic window without disturbance on the normal cardiovascular and respiratory physiology.


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: 2024 ( Subtotal = $0 )
2024	2022	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	2	6/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $70,500 )
2022	2022	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	2	2/7/2022	NON-COMPETING CONTINUATION	$70,500
														Subtotal = $70,500

Issue Date FY: 2021 ( Subtotal = $70,500 )
2021	2021	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	1	2/9/2021	NEW	$70,500
														Subtotal = $70,500

Grand Total All Awards = $141,000

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Chemoprevention of lung cancer with the β-blocker carvedilol

Award Number: R03CA256241

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2024

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