The oral glucocorticoid system in oral carcinogenesis and its modulation for improved treatment outcomes - PROJECT SUMMARY Oral cancer is a significant public health problem, as 58,450 new cases and 12,230 deaths occur annually. in the United States. Despite treatment advances, the overall survival rates (60% at 5 years, 50% at 10 years) for oral cancers have not appreciably changed over the past 30 years. Therefore, new and effective oral cancer chemoprevention and treatment strategies are needed. Although synthetic glucocorticoids are routinely used as adjuvant therapy in postoperative oral cancer patients, recent evidence indicates that glucocorticoids may actually promote tumor progression in some cases, thereby challenging the use of these compounds in patients with premalignant and malignant oral disease. Since glucocorticoid biosynthesis and regulation can occur in the oral mucosa, it is essential that we clearly understand the role of the oral glucocorticoid system on oral cancer development and metastasis. Further, we recently identified a potent cancer chemopreventive agent, gallic acid, which modulates glucocorticoid metabolism, but specific mechanisms associated with gallic acid mediated regulation of glucocorticoid metabolism during oral cancer chemoprevention is currently unknown. In this proposal, we propose to determine the mechanistic role of the oral glucocorticoid system on oral cancer development and metastasis and determine the effects of the chemopreventive agent gallic acid on the glucocorticoid metabolic pathway during oral cancer chemoprevention. We will use oral cancer cell lines, animal models and oral cancer clinical samples to determine these effects. Our hypothesis is that downregulation of the glucocorticoid inactivating enzyme, Hsd11b2, promotes active glucocorticoid signaling in the oral mucosa, which promotes cancer, and inhibition of this pathway by gallic acid can prevent oral cancer development and metastasis. Studies in aim 1 will define the impact of glucocorticoids and Hsd11b2 on oral cancer development and metastasis. We will use genetically modified mice, cell lines and patient samples, to determine how glucocorticoid metabolism affects oral carcinogenesis. Studies in aim 2 will determine the effect of glucocorticoid signaling on tumor cells and tumor infiltrating T cells during oral carcinogenesis. We will use genetically modified mice targeting the glucocorticoid receptor Nr3c1 on oral cancer cells and T cells for these studies. Studies in aim 3 will determine the effect of gallic acid on oral glucocorticoid metabolism during oral cancer, and how the regulation of glucocorticoid metabolism by gallic acid affects oral cancer outcomes. The complementary expertise of our investigative team coupled with novel experimental approaches will facilitate the successful completion of the aims proposed in this application. These studies will increase our understanding of how the oral glucocorticoid system affects oral carcinogenesis and the mechanisms of gallic acid mediated inhibition of oral cancer. Our studies also have the potential to change the current clinical practice of using synthetic glucocorticoids in oral cancer management.
