Developing new therapeutic strategies against head and neck cancer

开发针对头颈癌的新治疗策略

• 批准号: 10571845
• 负责人: Ratna B. Ray
• 金额: $ 48.37万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571845
• 关键词: Address; Aftercare; Animal Cancer Model; Animal Model; Apoptotic; Automobile Driving; Biochemical; Carcinogens; Cell physiology; Cells; Cessation of life; Cisplatin; Data; Disease; Epithelium; Etiology; Funding; Future; Global Change; Glucose; Grant; Growth; Head and Neck Cancer; Head and Neck Neoplasms; Heavy Drinking; Human papilloma virus infection; Immune; Immunocompetent; Immunosuppression; Knowledge; Lipids; Malignant Neoplasms; Mastication; Measures; Mediating; Melons; Metabolic Pathway; Modality; Modeling; Mucous Membrane; Mus; Natural Killer Cells; Natural Products; Operative Surgical Procedures; Pathway interactions; Patients; Phenotype; Pre-Clinical Model; Preventive; Process; Prognosis; Radiation therapy; Recurrence; Risk Factors; Risk Reduction; Role; Signal Transduction; Survival Rate; T-Lymphocyte; Testing; Therapeutic; Therapeutic Uses; Time; Tissues; Tobacco use; Treatment Efficacy; Untranslated RNA; Vaccination; World Health Organization; anti-PD1 antibodies; chemotherapy; efficacy evaluation; feeding; glucose metabolism; head and neck cancer patient; head and neck cancer prevention; immunoregulation; improved; innovation; lipid metabolism; malignant mouth neoplasm; metabolomics; mouse model; novel; novel therapeutic intervention; prevent; side effect; therapeutic development; therapeutically effective; transcriptomics; translational impact; treatment strategy; tumor; tumor growth; tumor metabolism; tumor microenvironment

Abstract Head and neck cancer (HNC) is the sixth most prevalent cancer in the world, and oral cancer is the most common subtype. The World Health Organization estimates ~330,000 deaths per year globally. The overall survival rate (50-60%) has not improved over the past couple of decades, despite significant improvements in surgical procedure, radiotherapy, and chemotherapy. The risk factors associated with oral cancer includes tobacco use, excessive alcohol consumption, betel quid chewing, and human papillomavirus (HPV) infection. HPV infection is likely to be reduced in the future due to successful vaccination and better prognosis. There is a critical need to define the HNC disease processes, and to identify better therapeutic strategies for successful HNC patient management. Further, non-traditional therapies must be investigated as adjuncts to reduce the risk of recurrence and improve survival. In our current funding period, we made several important novel observations. We showed that bitter melon extract feeding alters c-Met signaling and prevents HNC growth in preclinical models. We subsequently showed an immunomodulatory role of bitter melon extract, although the precise mechanism is yet to be determined. Further, we found several long non-coding RNAs are altered in feeding of bitter melon extract in a carcinogen-induced model. Very recently, we identified momordicine-I, one of the active metabolites of bitter melon, which shows therapeutic anti-tumor activity in an oral cancer preclinical model. Although we gained much evidence for bitter melon in prevention of HNC from our and other studies, considerable knowledge gaps remain in understanding the mechanism of momordicine-I on tumor metabolism and immune regulation, and its therapeutic use. Based on our and others results, we hypothesize that combining momordicine-I with other current therapeutics will improve efficacy in tumor regression. We will also examine the changes in glucose and lipid metabolism and the tumor microenvironment after treatment with momordicine-I using a mouse model. Results from this study will have important translational implications and significant benefits along with current therapy. Innovation: Our study will examine for the first time the therapeutic and mechanistic effects of momordicine-I in HNC animal models for major translational impact.

摘要 头颈癌是世界上第六大癌症，口腔癌是世界上最常见的癌症。 公共子类型。世界卫生组织估计，全球每年约有33万人死亡。整体而言 存活率(50%-60%)在过去几十年里没有改善，尽管在 外科手术、放射治疗和化疗。与口腔癌相关的危险因素包括 吸烟、过度饮酒、嚼槟榔和人类乳头瘤病毒(HPV)感染。 由于成功接种疫苗和更好的预后，未来HPV感染可能会减少。的确有 迫切需要确定HNC疾病的过程，并确定更好的治疗策略以获得成功 HNC患者管理。此外，必须将非传统疗法作为辅助手段进行研究，以减少 增加复发风险，提高存活率。在我们目前的资助期间，我们制作了几部重要的小说 观察。我们发现，苦瓜提取物喂养改变了c-Met信号转导，并阻止了HNC的生长 临床前模型。我们随后展示了苦瓜提取物的免疫调节作用，尽管 确切的机制尚不清楚。此外，我们发现几个长的非编码RNA在 苦瓜提取物对致癌物致癌动物模型的影响。就在最近，我们确定了苦瓜-I，一 苦瓜的活性代谢产物对口腔癌具有治疗肿瘤的活性 临床前模型。虽然我们获得了许多苦瓜预防HNC的证据，但我们的 研究表明，在理解苦瓜素-I治疗肿瘤的机制方面仍存在相当大的知识空白 代谢和免疫调节及其治疗应用。根据我们和其他人的结果，我们假设 将苦瓜素-I与其他目前的治疗方法相结合，将提高肿瘤消退的疗效。我们会 观察治疗前后糖脂代谢及肿瘤微环境的变化 使用的是一种小鼠模型。这项研究的结果将具有重要的翻译意义 与目前的治疗方法一起带来显著的好处。 创新：我们的研究将首次检验苦瓜素-I的治疗和机制作用 在HNC动物模型中有重大的翻译影响。