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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。全球每年有超过710,000例确诊病例，在美国，每年发生50,000多例新病例和10,000人死亡。尽管治疗取得了进展，但有5人与区域晚期和远处转移的口腔癌相关的一年生存率分别为50%和35% 分别进行了分析。新的治疗形式并没有显著提高头颈部癌症的存活率。因此，迫切需要新的、有效的口腔癌防治策略。虽然近年来，人工合成的糖皮质激素被常规用于口腔癌术后患者的辅助治疗。有证据表明，这些化合物在口腔癌前疾病和恶性口腔疾病患者中的使用受到了挑战。糖皮质激素的生物合成和调节已被证明发生在口腔粘膜。因此，它是必不可少的我们清楚地了解口腔糖皮质激素系统在口腔癌发生和转移中的作用。我们的最近的数据表明，黑树莓中预防口腔癌的化学植物化学物质可以调节口服糖皮质激素系统，但与此相关的具体机制目前尚不清楚。在这项提案中，我们将确定口服糖皮质激素系统对口腔癌发生和发展的影响。转移，并确定黑树莓植物化学物质对糖皮质激素代谢的影响口腔癌化学预防中的途径。我们的假设是口腔粘膜中糖皮质激素的激活促进口腔癌，而BRB植物化学物质抑制口腔癌细胞中的这一途径可以防止口腔癌癌症的发展和转移。目标1中的研究将明确定义口服糖皮质激素的影响口腔癌发生、发展和转移的系统。我们将使用条件单元格特定的和 Hsd11b2基因缺陷的可诱导基因敲除小鼠，Hsd11b2是参与活性糖皮质激素的关键酶失活，以确定糖皮质激素失活如何影响口腔癌的发生。AIM 2中的研究将确定黑莓植物化学物质在口腔癌期间对口腔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的预后。AIM 3中的研究将识别潜在的针对糖皮质激素代谢途径的黑莓植物化学物质这促进了口腔癌的化学预防。这些植物化学物质将被分离出来在口腔癌变的实验模型中进行了测试。我们调查团队的互补专业知识再加上我们新颖的实验方法，将有助于成功完成所提出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促进我们对黑树莓抑制口腔癌发生的机制的认识口腔癌。我们将确定潜在的调节糖皮质激素代谢的黑莓植物化学物质。用于治疗口腔炎症性疾病。我们的研究也有可能改变目前的合成皮质类固醇在口腔癌治疗中的临床应用。