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

定义口服糖皮质激素系统在口腔癌发生中的作用及其调节以改善治疗结果

基本信息

批准号：
10453480
负责人：
Steve Onyeka Oghumu
金额：
$ 56.14万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10453480
关键词：
Adjuvant Therapy Adrenal Cortex Hormones Affect Anabolism Antitumor Response Biological Assay Cancer Patient Carcinogenesis Inhibition Cell Proliferation Cells Cessation of life Chemoprevention Chemopreventive Agent Clinical Clinical Chemoprevention Clinical Research Coupled Data Development Diagnosis Disease Distant Enzymes Epithelial Cells Experimental Models Fractionation Gene Deletion Glucocorticoid Receptor Glucocorticoids Goals Head and Neck Cancer Immune Inflammatory Intervention Knockout Mice Knowledge Malignant - descriptor Malignant Neoplasms Mediating Metabolic Pathway Metabolism Mouth Diseases Mouth Neoplasms Mutant Strains Mice Neoplasm Metastasis Oral Oral mucous membrane structure Outcome Pathway interactions Patients Phytochemical Populations at Risk Positioning Attribute Postoperative Period Prevention strategy Preventive Public Health Raspberries Recurrence Regulation Resources Role Steroid Biochemistry Survival Rate System T-Lymphocyte Testing Therapeutic Treatment outcome United States advanced analytics anti-cancer anti-tumor immune response base bioactive natural products cancer cell cancer chemoprevention cancer initiation cancer therapy chemotherapeutic agent clinical practice conditional mutant dietary improved in vivo malignant mouth neoplasm metabolomics mouse model novel oral cancer prevention oral carcinogenesis oral tissue preclinical study premalignant prevent public health relevance response treatment strategy tumor tumor growth tumor progression

项目摘要

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.

项目摘要/摘要口腔癌是一个重大的公共卫生问题。每年全球诊断出710,000例案件，在美国，每年发生超过50,000例新病例和10,000例死亡。尽管有治疗进展，但5 与区域晚期和远转转移性口腔癌相关的年份生存率为50％和35％分别。新形式的治疗尚未显着提高头颈癌的存活率。因此，迫切需要新的有效的口腔预防和治疗策略。虽然合成糖皮质激素通常用作术后口腔癌患者的辅助治疗，最近证据是挑战这些化合物在口腔疾病和恶性口腔疾病的患者中的使用。糖皮质激素的生物合成和调节已显示出在口腔粘膜中。因此，这是必不可少的我们清楚地了解口服糖皮质激素系统在口服癌变和转移中的作用。我们的最近的数据表明，黑色覆盆子中的口腔癌化学预防化学物质可以调节目前尚不清楚口服糖皮质激素系统，但与该调节相关的具体机制。在此提案中，我们将确定口服糖皮质激素系统对口腔癌发展和转移，并确定黑色覆盆子植物化学物质对糖皮质激素代谢的影响口腔癌化学预防期间的途径。我们的假设是口服粘膜中的糖皮质激素激活促进口腔癌，并通过BRB植物化学物质在口腔癌细胞中抑制这种途径可以预防口服癌症发展和转移。 AIM 1中的研究将清楚地定义口服糖皮质激素的影响口腔癌发展，进展和转移的系统。我们将使用条件细胞特异性和可诱导的敲除hsd11b2不足的小鼠，这是一种参与活性糖皮质激素的键酶灭活，确定糖皮质激素失活如何影响口服癌变。 AIM 2的研究将确定黑色覆盆子植物化学物质对口腔癌期间口服糖皮质激素代谢的影响，以及BRB对糖皮质激素代谢的调节如何影响口腔癌预后。 AIM 3的研究将以某种方式识别靶向糖皮质激素代谢途径的潜在黑色覆盆子植物化学物质促进口腔癌变的口腔癌化学预防。这些植物化学物质将被隔离，并且在口服癌变的实验模型中进行了测试。我们调查团队的补充专业知识再加上我们的新实验方法，将有助于成功完成拟议的目标在此应用程序中。这些研究将增加我们对口服糖皮质激素系统如何影响的理解口服癌变并扩展我们对黑色覆盆子介导的抑制的机制的理解口腔癌。我们将确定潜在的黑色覆盆子植物化学物质，以调节糖皮质激素代谢用于管理口腔炎症性疾病。我们的研究也有可能改变电流在口腔癌管理中使用合成皮质类固醇的临床实践。