Food-Based Modulation of Biomarkers in Human Tissues at High-Risk for Oral Cancer

描述(由申请人提供)： 理论基础：一种以食物为基础的癌症化学预防方法强调了在整个食品中使用复杂的防腐剂混合物来抑制多种致癌过程的可能性。支持这一点的是，已经进行了几项临床前动物研究，证明了冻干黑树莓[LBR]对肿瘤发展(包括口腔癌)具有显著的化学预防活性。我们的初步数据表明，LBR的短期原位传递可以调节癌前患者癌细胞和高危正常口腔黏膜中关键调控基因的表达，这可能有助于预防癌症的发展。假设：头颈部[HN]癌症患者术后长期每日暴露于LBR将调节口腔癌发展过程中关键基因的表达。这种调节可能预测LBR在人类口腔癌发生中的预防潜力。实验方法：将在手术切除I期或II期HN癌后的210人中进行IB-IIA期手术后临床试验。在两个递送系统中每天给予LBR剂量(0，4，8克)，为期6个月。将在选定的时间点收集口腔刮片、血液、尿液和唾液，并评估黏附/暴露的结果、安全性/毒性以及调节与致癌进展相关的特定基因表达的能力。具体目标：目标1。确定手术后患者对临床试验设计期望的依从性，并确定长期服用LBR的耐受性和潜在的不良反应。目的2.确定口腔组织中LBR组分的暴露、剂量、载体和摄取之间的相互关系。目的3.评价LBR对口腔癌术后高危口腔黏膜基因表达的调节作用。目的4.分析LBR治疗停药后调控基因的持久性。这项新的转译研究将提供必要的数据，为实验和设计参数建立科学基础，纳入未来的第三阶段随机临床试验，并首次检验长期服用LBR对手术后癌症患者高危口腔粘膜的分子效应。它还将提供与可能导致口腔癌预防的关键基因调控相关的有价值的见解。 这项新的翻译研究将为未来的第三阶段随机临床试验中纳入的实验和设计参数提供必要的数据，并首次检验长期服用LBR对手术后癌症患者高危口腔粘膜的分子影响，并将提供与可能导致口腔癌症预防的关键基因调控有关的有价值的见解。

DESCRIPTION (provided by applicant): Rationale: A food-based approach to cancer chemoprevention emphasizes the potential for complex mixtures of preventive agents in whole foods to inhibit multiple processes of carcinogenesis. Supporting this, several preclinical animal studies have been conducted that demonstrate the remarkable chemopreventive activity of lyophilyzed black raspberries [LBR] on tumor development, including oral cancer. Preliminary data by us demonstrate that short-term in situ delivery of LBR can modulate the expression of key regulatory genes in cancer cells and "at-risk normal" oral mucosa of pre-surgical cancer patients that may favor the prevention of cancer development. Hypothesis: Long-term daily exposure of LBR by post-surgical head and neck [HN] cancer patients will modulate expression of genes critical in the development of oral cancer. This modulation may predict the preventive potential of LBR in human oral carcinogenesis. Experimental Approach: Phase IB- IIA post-surgical clinical trials will be conducted in 210 individuals following surgical resection of stage I or II HN cancers. Daily LBR doses (0, 4, 8 gm) in two delivery systems will be given for a period of six months. Oral cavity scrapings, blood, urine, and saliva will be collected at selected time points and evaluated for outcomes of adherance/exposure, safety/toxicity, and capacity to modulate specific gene expressions associated with carcinogenic progression. Specific Aims: Aim 1. Determine the adherence of post-surgical patients to clinical trial design expectations and define tolerability and, potential adverse effects of long-term LBR administration. Aim 2. Determine the interrelationships between exposure, dose and delivery vehicle, and uptake of LBR components in oral tissues. Aim 3. Evaluate the ability of LBR to modulate gene expression in high-risk oral mucosa of post-surgical oral cancer. Aim 4. Analyze for the persistence of modulation genes following cessation of LBR treatment. This novel translational study will provide essential data establishing the scientific foundation for experimental and design parameters to be included in a future Phase III randomized clinical trial and is the first to examine the molecular effects of long-term LBR administration on at-risk oral mucosa in post-surgical cancer patients. It will also provide valuable insights related to the modulation of critical genes that might lead to oral cancer prevention. This novel translational study will provide essential data establishing the scientific foundation for experimental and design parameters to be included in a future Phase III randomized clinical trial and is the first to examine the molecular effects of long-term LBR administration on at-risk oral mucosa in post-surgical cancer patients and will provide valuable insights related to the modulation of critical genes that might lead to oral cancer prevention.