Mechanistic Insights of BME mediated inhibition of head and neck cancer growth

 描述（由申请人提供）：头颈部鳞状细胞癌（HNSCC）是指一组生物学相似的癌症，起始于唇、舌、口腔（口）、鼻腔（鼻内）、鼻旁窦、咽和喉。HNSCC是全球第六大常见癌症，约占美国所有癌症的3-5%。美国癌症协会估计，2014年将有55,070人患头颈癌。HNSCC患者的5年生存率约为60%，在过去几十年中仅略有改善。尽管手术技术、化疗和放疗以及支持性治疗的改进改善了HNSCC患者的生活质量，但区域和远处复发仍然很常见，几乎总是致命的。目前HNSCC的细胞毒性疗法的影响受到疾病复发和对疗法的抗性的限制。因此，非常需要开发靶向和有效的疗法。我们最近发现了一种植物来源的天然产物，苦瓜提取物（BME），它可以诱导HNSCC细胞死亡。我们观察到BME处理HNSCC细胞抑制c-Met/EGFR和下游信号分子（Stat 3、c-myc和Mcl-1），并增强自然杀伤（NK）细胞活性，暗示其在抑制头颈癌中的潜在作用。本项目的长期目标是评估BME对HNSCC的预防和治疗效果，并了解其潜在机制。我们假设BME及其活性成分将通过多种机制预防和抑制HNSCC，包括：调节对癌症进展至关重要的基因，对临床前动物模型中的癌症干细胞样细胞和肿瘤微环境的影响。这项研究的结果将扩展并将我们的发现转化为未来的临床研究。创新：我们的申请将首次在高度相关的HNSCC动物模型中检查BME的机制，预防和治疗效果。

 DESCRIPTION (provided by applicant): Head and neck squamous cell carcinoma (HNSCC) refers to a group of biologically similar cancers that start in the lip, tongue, oral cavity (mouth, nasal cavity (inside the nose), paranasal sinuses, pharynx, and larynx. HNSCC is the sixth most common cancer worldwide, and accounts for about 3-5% of all cancers in the United States. American Cancer society estimates 55,070 people will develop head and neck cancers in 2014. The 5- year survival rate of HNSCC patients is ~60% and has improved only marginally during the past few decades. Although improvements in surgical techniques, chemotherapy and radiation delivery, and supportive care have improved quality of life for patients with HNSCC, the regional and distant recurrence remain common and is almost always fatal. The impact of current cytotoxic therapies for HNSCC is limited by disease recurrence and resistance to therapy. Thus, there is a tremendous need for development of targeted and effective therapies. We have recently identified a plant-derived natural product, bitter melon extract (BME), which can induce HNSCC cell death. We have observed that BME treatment on HNSCC cells inhibits c-Met/EGFR and downstream signaling molecules (Stat3, c-myc and Mcl-1), and enhances natural killer (NK) cell activity, implicating its potential role in inhibition of head and neck cacer. The long-term objective of our project is to evaluate preventive and therapeutic efficacy of BME against HNSCC and understanding the underlying mechanisms. We hypothesize that BME and its active component(s) will prevent and inhibit HNSCC by multiple mechanisms including: modulation of genes critical to cancer progression, effect on cancer stem-like cells and tumor microenvironment in preclinical animal models. Results from this study will extend and translate our findings to future clinical studies. Innovation: Our application will examine for the first tim the mechanistic, preventive, and therapeutic effect of BME in highly relevant HNSCC animal models.