Chemoprevention of Head & Neck Cancer

项目摘要-项目1 治疗与烟草相关的头颈部鳞状细胞癌(HNSCC)的长期成功是 在治疗后，第二原发瘤(SPT)的发展速度令人震惊。 人乳头瘤病毒(HPV)阴性的HNSCC患者发生上呼吸道SPT 每年3-6%的比率，并且最有可能死于这些继发性癌症。虽然吸烟 戒烟可减少SPTS的发生，5年内未观察到风险的缓和，且不足以 将风险恢复到基线。预防SPTS的耐受性良好且负担得起的干预措施的可用性将 对高危患者的死亡率和生活质量有重大的全球影响。不幸的是，没有可容忍的和 已经确定了有效的HNSCC化学预防药物。我们广泛的、长期的目标是严格 针对HNSCC SPTS的可耐受和有效的化学预防策略的翻译开发。 减少HNSCC和SPTS的风险与富含十字花科十字花科植物的饮食有关 蔬菜，包括西兰花。西兰花富含葡萄糖萝卜素，它被代谢成关键的生物活性物质。 萝卜硫素组分(SF)。SF诱导转录因子NRF2的表达，从而导致 上调NRF2靶基因。许多NRF2靶基因编码细胞保护酶，这些酶 采取行动消除环境致癌物质，包括烟草中的苯、醛和亚硝胺 烟。NRF2信号通路与口腔癌化学预防的相关性通过 Nrf2基因缺失小鼠对致癌物4NQO诱发口腔癌的易感性增强。我们是 西兰花种子制剂(BSP)作为化学预防致癌物的研究进展 并确定了BSP在人体内的安全性、耐受性和药代动力学。我们还有 结果表明，SF可诱导正常口腔角质形成细胞和HNSCC中NRF2和NRF2靶基因的表达 细胞系。此外，我们首次提供了NRF2靶基因的转录本是 富含SF的BSP治疗的健康志愿者口腔黏膜中表达上调。我们假设NRF2 根治性治疗的患者给予BSP可诱导口腔上皮细胞通路激活 第一，与烟草相关的HNSCC，以及NRF2通路激活的靶水平用于化学预防 人类的疗效可以在致癌物诱导的HNSCC的小鼠模型中确定。为了测试这一点 假设我们提出了两个具体目标：1)研究剂量-反应关系 萝卜硫素(SF)和致癌物诱导的HNSCC小鼠模型的化学预防效果，以及2) 系统评估BSP对烟草患者的临床化学预防潜力 相关的HNSCC是SPT的高危人群。

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.