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

描述（由申请人提供）： 基本原理：以食物为基础的癌症化学预防方法强调了完整食物中预防剂的复杂混合物抑制多种致癌过程的潜力。支持这一点，已经进行了几项临床前动物研究，证明了冻干黑树莓[LBR]对肿瘤发展的显着化学预防活性，包括口腔癌。我们的初步数据表明，LBR的短期原位递送可以调节癌细胞和术前癌症患者的“高危正常”口腔粘膜中关键调控基因的表达，这可能有利于预防癌症的发展。假设：头颈部[HN]癌术后患者长期每日暴露于LBR将调节口腔癌发展中关键基因的表达。这种调节可能预示LBR在人类口腔癌发生中的预防潜力。实验方法：IB-IIA期手术后临床试验将在手术切除I期或II期HN癌症后的210名个体中进行。每日LBR剂量（0，4，8 gm）在两个交付系统将给予为期六个月。将在选定的时间点采集口腔刮片、血液、尿液和唾液，并评价粘附/暴露、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的结局。具体目标：目标1。确定术后患者对临床试验设计预期的依从性，并确定长期LBR给药的耐受性和潜在不良反应。目标2.确定暴露、剂量和递送载体与口腔组织中LBR组分摄取之间的相互关系。目标3：评估LBR调节术后口腔癌高危口腔粘膜中基因表达的能力。目标4。分析LBR治疗停止后调节基因的持续性。这项新的转化研究将提供必要的数据，为未来III期随机临床试验中纳入的实验和设计参数建立科学基础，并且是第一个研究长期LBR给药对术后癌症患者中高危口腔粘膜的分子效应。它还将提供与调节可能导致口腔癌预防的关键基因相关的有价值的见解。 这项新的转化研究将提供必要的数据，为未来III期随机临床试验中纳入的实验和设计参数建立科学基础，并且是第一个研究长期LBR给药对术后癌症患者中高危口腔粘膜的分子效应的研究，并将提供与可能导致口腔癌预防的关键基因的调节相关的有价值的见解。

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.