Chemoprevention of Head & Neck Cancer

项目摘要-项目1 长期成功治疗烟草相关的头颈部鳞状细胞癌（HNSCC）， 受到治愈性治疗后第二原发性肿瘤（SPT）发展的惊人速度的阻碍。 人乳头瘤病毒（HPV）阴性的HNSCC患者在24小时发生上呼吸消化道SPT， 每年的发病率为3-6%，并且最有可能死于这些继发性癌症。虽然吸烟 停止使用可减少SPT的发生，5年内未观察到风险的适度， 将风险恢复到基线水平。提供耐受性良好且负担得起的预防SPT的干预措施， 对高危患者的死亡率和生活质量具有重大的全球影响。不幸的是，没有容忍和 已经鉴定出HNSCC的有效化学预防剂。我们广泛的长期目标是 针对HNSCC SPT的可耐受且有效的化学预防策略的翻译开发。 HNSCC和SPT的风险降低与富含十字花科芸苔属植物的饮食有关 蔬菜，包括花椰菜。西兰花中含有丰富的萝卜硫苷，是代谢产生生物活性的关键 组分莱菔硫烷（SF）。SF诱导转录因子NRF 2的表达，这导致 NRF 2靶基因的上调。许多NRF 2靶基因编码细胞保护酶， 对环境致癌物质包括烟草中的苯、醛和亚硝胺进行解毒 抽烟NRF 2信号通路与口腔癌化学预防的相关性由以下文献强调： 缺乏Nrf 2基因的小鼠对致癌物4 NQO诱导的口腔癌的易感性增强。我们 开发西兰花种子制剂（BSPs）作为一种化学预防剂， 癌症，并确定了安全性，耐受性，和人类的BSP的药代动力学。我们还 表明SF诱导正常口腔角质形成细胞和HNSCC中NRF 2和NRF 2靶基因表达 细胞系此外，我们首次证明了NRF 2靶基因的转录本是 在用富含SF的BSP治疗的健康志愿者的口腔粘膜中上调。我们假设NRF 2 通过对接受治疗的患者给予BSP，可以诱导口腔上皮细胞中的通路激活， 第一个烟草相关的HNSCC，和NRF 2途径激活的目标水平，化学预防 可以在致癌物诱导的HNSCC的小鼠模型中测定对人类的功效。为了验证这一 假设我们提出了两个具体的目的：1）调查剂量反应关系之间 萝卜硫素（SF）和致癌物诱导的HNSCC小鼠模型中的化学预防功效，以及2） 系统地评估BSP给药对吸烟患者的临床化学预防潜力， 相关HNSCC的SPT高风险。

Project Summary - Project 1 Long-term success in the treatment of tobacco-related head and neck squamous cell carcinoma (HNSCC) is hindered by an alarming rate of second primary tumor (SPT) development following curative treatment. Patients with human papillomavirus (HPV)-negative HNSCC develop a SPT of the upper aerodigestive tract at the rate of 3-6% per year, and are most likely to succumb to these secondary cancers. Although smoking cessation reduces the occurrence of SPTs, moderation of risk is not observed for 5 years, and is insufficient to return risk to baseline. The availability of a well-tolerated and affordable intervention that prevents SPTs would have a major global impact on mortality and quality of life in patients at risk. Unfortunately, no tolerable and effective chemopreventive agents have been identified for HNSCC. Our broad, long-term goal is the rigorous translational development of a tolerable and effective chemoprevention strategy against HNSCC SPTs. Reduced risk for HNSCC and SPTs is associated with diets rich in the Brassica family of cruciferous vegetables, including broccoli. Broccoli is rich in glucoraphanin, which is metabolized to the key bioactive component sulforaphane (SF). SF induces the expression of the transcription factor NRF2, which leads to upregulation of NRF2 target genes. A number of NRF2 target genes encode cytoprotective enzymes, which act to detoxify environmental carcinogens including benzene, aldehydes and nitrosamines found in tobacco smoke. The relevance of the NRF2 signaling pathway for oral cancer chemoprevention is highlighted by the enhanced susceptibility of mice lacking the Nrf2 gene to oral cancer induced by the carcinogen 4NQO. We are developing broccoli seed preparations (BSPs) as a chemopreventive agent against carcinogen-induced cancers, and have determined the safety, tolerability, and pharmacokinetics of BSPs in humans. We have also shown that SF induces NRF2 and NRF2 target gene expression in normal oral keratinocytes and in HNSCC cell lines. Moreover, we have provided first-time demonstration that transcripts for NRF2 target genes are upregulated in the oral mucosa of healthy volunteers treated with SF-rich BSP. We hypothesize that NRF2 pathway activation in oral epithelium can be induced by administering BSP to patients curatively treated for a first tobacco-related HNSCC, and that the target level of NRF2 pathway activation for chemopreventive efficacy in humans can be determined in a mouse model of carcinogen-induced HNSCC. To test this hypothesis we propose two Specific Aims: 1) To investigate the dose-response relationship between sulforaphane (SF) and chemopreventive efficacy in a mouse model of carcinogen-induced HNSCC, and 2) To systematically assess the clinical chemopreventive potential of BSP administration to patients with tobacco- related HNSCC at high risk for SPT.