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Combinational Approaches to the Chemoprevention of Esophageal Cancer

Award Number: R01CA131073
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2008
PERIOD OF PERFORMANCE END DATE: 05/31/2013

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Combinational Approaches to the Chemoprevention of Esophageal Cancer - DESCRIPTION (provided by applicant): Esophageal cancer is the 6th most common malignant neoplasm worldwide with more than 90% of all cases being esophageal squamous cell carcinoma (SCC). Risk factors for esophageal SCC include tobacco use, alcohol consumption, nutritional deficiency, and intake of food contaminated with various mycotoxins. Esophageal SCC grows more quickly than other kinds of gastrointestinal malignancies and patients with this disease have a very poor prognosis. Although surgery, chemotherapy, and radiotherapy alone or combined are used, the overall 5-year survival rate for this disease is still very low, ranging from 5% to 15%. To decrease the incidence of esophageal cancer, cancer chemoprevention through dietary and/or chemical intervention would be a logical and practical approach. Numerous compounds have been tested; however, the trails to date have not resulted in a decrease of esophageal cancer incidence. There is an urgent need to identify protective agents, which can prevent this disease in the individuals associated with increasing esophageal cancer risk. The long-term goal of our studies is to develop mechanism-driven safe and effective prevention strategies for reducing the incidence of esophageal cancer in high-risk populations. N-nitrosomethylbenzylamine (NMBA)- induced rat preclinical model of esophageal cancer has been used extensively to investigate the mechanisms of esophageal carcinogenesis and to evaluate the efficacy of potential chemopreventive agents. The multistage evolution of esophageal SCC, from normal to hyperplasia, dysplasia and papilloma, is ideal for the application of chemoprevention strategies. In this proposal, we outline our strategy to develop combinational approaches to the chemoprevention of esophageal cancer. Our central hypothesis is that combination of cyclooxygenase-2 (COX-2) inhibitor, celecoxib, inducible nitric oxide synthase (iNOS) inhibitor, S,S'-1,4- phenylene-bis(1,2-ethanediyl)bis-isothiourea (PBIT), and freeze-dried black raspberries (BRB) will increase efficacy against tumor development while minimizing toxicity in NMBA-rat preclinical model. The specific aims are: 1. To establish strategies to improve efficacy of esophageal cancer prevention by a combination of COX-2 and iNOS inhibitors; 2. To establish strategies to improve efficacy of esophageal cancer prevention by a combination of pure compound(s) and natural food product and to determine the cellular and molecular mechanisms of their actions; 3. To investigate the roles of mitogen-activated protein kinase (MAPK) and nuclear factor :B (NF:B) pathways in NMBA-induced tumorigenesis in the rat esophagus. Overall, a successful outcome of this hypothesis-driven preclinical study will provide important information and rationale to develop a combination with agents that may have synergistic activity in human clinical trials of chemoprevention of esophageal cancer. PUBLIC HEALTH RELEVANCE: The overall objective of this project is to evaluate the efficacy of combinational approaches against esophageal cancer development, to investigate the mechanistic basis of these agents, and to identify cellular and molecular biomarkers of esophageal tumorigenesis using a rat preclinical model, which is highly analogous to human esophageal squamous cell carcinoma.


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: 2015 ( Subtotal = $0 )
2015	2012	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	5	7/27/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $0 )
2014	2012	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	5	6/11/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $301,913 )
2012	2012	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	5	5/24/2012	NON-COMPETING CONTINUATION	$301,913
														Subtotal = $301,913

Issue Date FY: 2011 ( Subtotal = $381,022 )
2011	2011	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	001	4	9/19/2011	SUPPLEMENT FOR EXPANSION	$79,109
2011	2011	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	4	6/1/2011	NON-COMPETING CONTINUATION	$301,913
														Subtotal = $381,022

Issue Date FY: 2010 ( Subtotal = $311,250 )
2010	2010	OHIO STATE UNIVERSITY	1800 CANNON DR/700 LINCOLN TOW	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	3	5/26/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$311,250
2010	2009	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	001	2	5/26/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $311,250

Issue Date FY: 2009 ( Subtotal = $311,250 )
2009	2009	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	2	5/20/2009	NON-COMPETING CONTINUATION	$311,250
														Subtotal = $311,250

Issue Date FY: 2008 ( Subtotal = $311,250 )
2008	2008	OHIO STATE UNIVERSITY, RESEARCH FOUNDATION	1960 KENNY ROAD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Cause and Prevention Research	000	1	5/9/2008	NEW	$311,250
														Subtotal = $311,250

Grand Total All Awards = $1,616,685

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Combinational Approaches to the Chemoprevention of Esophageal Cancer

Award Number: R01CA131073

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2008

PERIOD OF PERFORMANCE END DATE: 05/31/2013

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