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

 描述(申请人提供)：头颈部鳞状细胞癌(HNSCC)是指一组生物学上相似的癌症，起始于嘴唇、舌头、口腔(口腔)、鼻腔(鼻子内)、副鼻窦、咽和喉部。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人患上头颈部癌症。HNSCC患者的5年生存率约为60%，在过去的几十年里只有轻微的改善。尽管在手术技术、化疗和放射治疗以及支持性治疗方面的改进提高了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。目前细胞毒治疗对HNSCC的影响受到疾病复发和治疗抵抗的限制。因此，非常需要开发有针对性和有效的治疗方法。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对HNSCC细胞的作用抑制了c-Met/EGFR及其下游信号分子(STAT3、c-myc和Mcl-1)，并增强了自然杀伤(NK)细胞的活性，暗示了其在抑制头颈部癌中的潜在作用。我们项目的长期目标是评估BME对HNSCC的预防和治疗效果，并了解其潜在的机制。我们推测BME及其活性成分(S)可能通过多种机制预防和抑制HNSCC，包括对肿瘤进展关键基因的调控、对肿瘤干细胞的影响以及临床前动物模型中肿瘤微环境的影响。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：我们的应用将首次在高度相关的HNSCC动物模型中检验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.