Defining the role of the oral glucocorticoid system in oral carcinogenesis and its modulation for improved treatment outcomes

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PROJECT SUMMARY/ABSTRACT Oral cancer is a significant public health problem. Over 710,000 cases are diagnosed globally each year, and in the United States, over 50,000 new cases and 10,000 deaths occur annually. Despite treatment advances, 5 year survival rates associated with regionally advanced and distantly metastatic oral cancer are 50% and 35% respectively. New forms of treatment have not significantly improved head and neck cancer survival rates. Therefore, new and effective oral cancer prevention and treatment strategies are desperately needed. Although synthetic glucocorticoids are routinely used as adjuvant therapy in postoperative oral cancer patients, recent evidence is challenging the use of these compounds in patients with premalignant and malignant oral disease. Glucocorticoid biosynthesis and regulation have been shown to occur in the oral mucosa. It is therefore essential that we clearly understand the role of the oral glucocorticoid system on oral carcinogenesis and metastasis. Our recent data suggests that the oral cancer chemopreventive phytochemicals in black raspberries can modulate the oral glucocorticoid system, but the specific mechanisms associated with this regulation is currently unknown. In this proposal, we will determine the impact of the oral glucocorticoid system on oral cancer development and metastasis, and determine the effects of black raspberry phytochemicals on the glucocorticoid metabolic pathway during oral cancer chemoprevention. Our hypothesis is that glucocorticoid activation in the oral mucosa promotes oral cancer, and inhibition of this pathway in oral cancer cells by BRB phytochemicals can prevent oral cancer development and metastasis. Studies in aim 1 will clearly define the impact of the oral glucocorticoid system on oral cancer development, progression and metastasis. We will use conditional cell specific and inducible knock out mice that are deficient in Hsd11b2, a key enzyme involved in active glucocorticoid inactivation, to determine how glucocorticoid inactivation affects oral carcinogenesis. Studies in aim 2 will determine the effect of black raspberry phytochemicals on oral glucocorticoid metabolism during oral cancer, and how the regulation of glucocorticoid metabolism by BRB affects oral cancer outcomes. Studies in aim 3 will identify potential black raspberry phytochemicals that target the glucocorticoid metabolic pathway in a manner that promotes oral cancer chemoprevention of oral carcinogenesis. These phytochemicals will be isolated and tested in experimental models of oral carcinogenesis. The complementary expertise of our investigative team coupled with our 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 expand our understanding of the mechanisms of black raspberry mediated inhibition of oral cancer. We will identify potential black raspberry phytochemicals that modulate glucocorticoid metabolism for the management of oral inflammatory diseases. Our studies also have the potential to change the current clinical practice of using synthetic corticosteroids in oral cancer management.