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Grant Abstract

Grant Number: 5R01CA095568-05
Project Title: Biomarkers to Assess Selenium Chemoprevention for NSCLC

Abstract: DESCRIPTION (provided by applicant): Mortality from lung cancer could be reduced through implementation of strategies to reverse or impede I premalignant disease. Ingestion of L-selenomethionine has been associated with a 50% decrease in expected rates of lung cancer. ECOG 5597, "A Phase III Chemoprevention Trial of Selenium in Persons with Resected Stage I NSCLC," will test the hypothesis that selenium can decrease the rate of second primary tumors in patients who have undergone surgery for stage I NSCLC. Selenium may prevent lung cancer by protecting tissue from oxidative damage, inducing apoptosis, and/or by acting as a demethylating agent through inhibition of cytosine DNAmethyltransferase (DNMT). In support of the latter mechanism, our studies demonstrate a dose response for the reexpression of the p16 gene in lung cancer cell lines following treatment with selenium. The identification of biomarkers that predict the efficacy of selenium would aid in the validation of this agent as a chemopreventive. We have targeted genes inactivated by CpG island methylation as candidate biomarkers and demonstrated that methylation of genes such as p16 may predict lung cancer risk and be used to monitor the efficacy of preventive agents. We have recently been awarded a grant CA95568, "Biomarkers to Assess Selenium Chemoprevention for NSCLC" to use gene methylation as a molecular marker system to evaluate the efficacy of selenium intervention and to predict development of a second primary tumor. The potential for modulating promoter methylation therapeutically was endorsed through a study demonstrating that inhibitors of DNMTs and histone deacetylation (HDAC) can act synergistically to reexpress genes silenced by promoter methylation. We have extended this finding to demonstrate a synergistic effect of deoxyazacytidine and sodium phenylbutyrate (HDAC inhibitor) in the prevention of mouse lung tumor formation. Selenium with an HDAC inhibitor could be a combined approach to prevent lung cancer. Nutrition may also interact directly or indirectly to impact promoter methylation. Three aims will address the hypothesis of this supplemental grant: that selenium's anticarcinogenic properties are mediated in part, by affects on aberrant promoter methylation. Aim 1 will determine whether diet is associated with detecting promoter methylation in sputum and/or plasma from persons enrolled in the selenium trial. Aim 2 will determine whether selenium-mediated reexpression of genes silenced by hypermethylation occurs through promoter demethylation alone, or in combination with modification of the histone code. Finally, aim 3 will determine the potency of selenium alone and in concert with HDAC inhibitors to prevent lung cancer development and to impede the progression of field cancerization in a murine lung tumor model.

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