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.

抽象的 头颈癌（HNC）是世界上第六大流行的癌症，口腔癌是最常见的癌症 常见的亚型。世界卫生组织每年估计全球约330,000人死亡。总体 在过去的几十年中，生存率（50-60％）尚未提高，尽管显着提高了 外科手术，放疗和化学疗法。与口腔癌有关的危险因素包括 烟草使用，饮酒过多，槟榔咀嚼和人乳头瘤病毒（HPV）感染。 由于成功的疫苗接种和更好的预后，将来可能会降低HPV感染。有 定义HNC疾病过程并确定成功的治疗策略的迫切需要 HNC患者管理。此外，必须研究非传统疗法作为辅助疗法以减少 复发的风险并改善生存。在当前的资金期间，我们制作了几本重要的小说 观察。我们表明，苦瓜提取物的喂养会改变C-MET的信号传导，并防止HNC的生长 临床前模型。随后，我们表现出苦瓜提取物的免疫调节作用，尽管 精确的机制尚待确定。此外，我们发现几个长的非编码RNA在 在致癌物诱导的模型中进食苦瓜提取物。最近，我们确定了Momordicine-I，一个 苦瓜的活性代谢产物，该代谢物显示出口腔癌的治疗性抗肿瘤活性 临床前模型。尽管我们为预防HNC从我们的和其他方面提供了很多证据 研究，知识差距仍然存在于理解Momordicine-I对肿瘤的机制 代谢和免疫调节及其治疗用途。根据我们的和其他结果，我们假设 将Momordicine-I与其他当前治疗剂相结合的将提高肿瘤回归的功效。我们将 还要检查治疗后葡萄糖和脂质代谢的变化以及肿瘤微环境的变化 使用Momordicine-I使用鼠标模型。这项研究的结果将具有重要的翻译意义 以及当前疗法的重大好处。 创新：我们的研究将首次研究Momordicine-I的治疗和机械作用 在HNC动物模型中，用于重大翻译影响。