Developing new therapeutic strategies against head and neck cancer

摘要 头颈癌（HNC）是世界上第六大流行癌症，口腔癌是最常见的癌症。 常见亚型世界卫生组织估计，全球每年约有33万人死亡。整体 在过去的几十年里，生存率（50 - 60%）并没有提高，尽管在以下方面有了显著的改善： 外科手术、放疗和化疗。与口腔癌相关的风险因素包括 吸烟、过量饮酒、嚼槟榔和人乳头瘤病毒（HPV）感染。 由于疫苗接种成功和预后更好，HPV感染在未来可能会减少。有 迫切需要定义HNC疾病过程，并确定更好的治疗策略， HNC患者管理。此外，必须研究非传统疗法，以减少 降低复发风险，提高生存率。在我们目前的资助期间，我们制作了几部重要的小说， 意见。我们发现，苦瓜提取物喂养改变了c-Met信号传导，并阻止了HNC的生长。 临床前模型。我们随后显示了苦瓜提取物的免疫调节作用，尽管 确切的机制尚待确定。此外，我们还发现一些长的非编码RNA被改变， 在致癌物诱导的模型中喂食苦瓜提取物。最近，我们发现了苦参碱， 苦瓜的活性代谢物，其在口腔癌中显示出治疗性抗肿瘤活性， 临床前模型虽然我们从国内外获得了苦瓜预防HNC的大量证据， 目前的研究表明，在了解苦参碱-I对肿瘤的作用机制方面仍存在相当大的知识空白 代谢和免疫调节，及其治疗用途。根据我们和其他人的研究结果，我们假设 将苦参碱-I与其他现有疗法结合将提高肿瘤消退的功效。我们将 并检测治疗后糖脂代谢及肿瘤微环境的变化 使用小鼠模型。这项研究的结果将具有重要的翻译意义 和显著的益处沿着当前疗法。 创新：我们的研究将首次检查莫马林-I的治疗和机制作用。 在HNC动物模型中的主要翻译影响。

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.