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Electronic cigarette derived free radicals, oxidative stress and inflammation in lung cancer development

Award Number: R01CA270608
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Electronic cigarette derived free radicals, oxidative stress and inflammation in lung cancer development - Electronic cigarettes (e-cig) have been promoted as electronic nicotine (NIC) delivery systems (ENDS) without the adverse effects of tobacco cigarette smoking (CS). However, recent studies have reported a wide range of e-cig-induced toxicities with severe inflammatory lung disease observed in e-cig users. While there is a strong association between CS-induced oxidative stress, inflammation and cancer, this has not been established for e-cig use. E-cig generate toxic species, including free radicals and reactive aldehydes with the levels of these toxicants increased with increasing device power. These toxic chemicals produce reactive oxygen species (ROS), which can lead to uncontrolled inflammation and DNA damage with dysregulated cell proliferation that trigger carcinogenesis. In our chronic mouse e-cig exposure model, we observed that e-cig aerosol, generated from e-cig liquid containing NIC, induced lung tumors in 50% of the mice studied at 50 weeks of exposure, as first detected by micro-CT imaging. Histopathological examination of the tumors showed adenocarcinoma or adenoma with focal mixed broncho-alveolar neoplastic and pre-malignant cells. Superoxide radicals, inflammation, DNA damage and stemness markers were detected in the alveoli and bronchioles, preceding cancer development at earlier exposure times. The free radicals and high levels of aldehydes in e-cig aerosol, as well as the NIC derived iminium metabolite, can trigger processes of cellular ROS generation and this may serve as a central trigger of carcinogenesis. Based on the critical public health implications of this work, it is imperative to expand these observations to measure the exposure intensity/duration relationships, and the role of e-cig aerosol free radical levels and NIC in cancer development. Thus, we will perform longitudinal studies with the requisite group size needed to definitively address the critical questions: 1) What is the exposure intensity and duration required for lung cancer initiation/progression? 2) What is the incidence rate of e-cig-induced lung cancer? 3) Is cancer onset and/or progression NIC-dependent? 4) How is it effected by device power and resultant aerosol free radical levels? 5) Is cancer onset and/or progression sex-dependent? 6) What are the mechanisms by which e-cig exposure triggers ROS generation and inflammation in the lung? Studies with longitudinal micro-CT, MRI, EPR spectroscopy, EPRMRI co-imaging and blood tumor markers followed by biochemical assays and histopathology will determine the role of exposure duration, ENDS power, NIC, and sex on initiation and/or progression of lung cancer. ROS generation, lung inflammation and secondary epithelial mesenchymal transition will be evaluated as triggers or steps leading to carcinogenesis. With knowledge of the role of these mechanisms and evaluation of inhibitors that block them, we will identify therapeutic interventions that could be used to ameliorate e-cig induced lung inflammation and carcinogenesis. Thus, this research will provide important insights defining the carcinogenesis risk of e-cig use, and its underlying exposure-dependent triggers and mechanisms.


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 = $565,464 )
2026	2026	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	5	2/25/2026	NON-COMPETING CONTINUATION	$565,464
														Subtotal = $565,464

Issue Date FY: 2025 ( Subtotal = $565,464 )
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	001	4	5/23/2025	NON-COMPETING CONTINUATION	$56,545
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	4	2/14/2025	NON-COMPETING CONTINUATION	$508,919
														Subtotal = $565,464

Issue Date FY: 2024 ( Subtotal = $537,192 )
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	3	1/31/2024	NON-COMPETING CONTINUATION	$508,919
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	001	3	4/17/2024	NON-COMPETING CONTINUATION	$28,273
														Subtotal = $537,192

Issue Date FY: 2023 ( Subtotal = $554,155 )
2023	2023	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	2	2/9/2023	NON-COMPETING CONTINUATION	$554,155
														Subtotal = $554,155

Issue Date FY: 2022 ( Subtotal = $565,464 )
2022	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	1	3/15/2022	NEW	$565,464
														Subtotal = $565,464

Grand Total All Awards = $2,787,739

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Electronic cigarette derived free radicals, oxidative stress and inflammation in lung cancer development

Award Number: R01CA270608

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/15/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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