Lung cancer is increasingly becoming a disease which occurs in former smokers. Approximately 50% of lung cancers currently happen in former smokers and, as the number of quitters continues to grow (currently 44 million in the U.S.), this will become an increasing health care problem. Strategies must be devised to reduce lung cancer risk in this population through the identification of high risk individuals and the development of effective lung cancer chemoprevention treatments. To begin to address these issues, this proposal will examine the efficacy of 9-cis retinoic acid (9cRA) in the reversal of bronchial metaplasia and dysplasia in former smokers. This randomized, placebo-controlled trial will require 80 evaluable patients (40 per arm). Our prior studies have shown that 13-cis retinoic acid (13cRA) can reverse oral premalignancy and inhibit second primary tumors in patients with a prior head and neck malignancy. This proposal will begin to examine the role of retinoids in lung cancer prevention using 9cRA, a novel naturally-occurring retinoid with unique retinoid receptor affinities. Unlike other known retinoids 9cRA can bind both RARs and RXRs, suggesting that 9cRA may have biologic effects not possible with other retinoids. To examine the role of specific retinoid receptors, RNA in situ studies of retinoid receptor (RAR, RXR and LXR) expression will be performed on bronchial biopsies obtained before and after retinoid treatment, and changes in receptor expression will be correlated with clinical outcome (reversal of bronchial metaplasia and dysplasia). In addition, more mechanistic studies will be performed in vitro on normal, premalignant, and malignant human bronchial epithelial (HBE) cells to examine the effects of a variety of receptor-specific synthetic retinoids on receptor expression and function (DNA binding and transcriptional activation). These effects will be correlated with retinoid-induced changes in HBE cellular growth and squamous differentiation. Through these studies we hope to begin to understand the role of specific receptors in the control of HBE cellular growth and differentiation and to identify retinoids which are more efficacious in lung cancer prevention. With this trial, we will address the following specific aims:
Specific Aim 1 : To confirm the persistence of premalignant bronchial lesions in former smokers by measuring their incidence and severity.
Specific Aim 2 : To determine the efficacy of 9cRA in reversing bronchial metaplasia and/or dysplasia.
Specific Aim 3 : To correlate in vivo and in vitro the reversal of bronchial epithelial abnormalities with retinoid receptor activation.
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