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

描述（由申请人提供）： 理由：基于食物的癌症化学预防方法强调天然食品中预防剂的复杂混合物抑制多种致癌过程的潜力。支持这一点的是，已经进行的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）具有显着的化学预防活性。我们的初步数据表明，短期原位递送 LBR 可以调节癌细胞和术前癌症患者“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发展。假设：头颈癌 [HN] 癌症术后患者每天长期接触 LBR 将调节对口腔癌发展至关重要的基因表达。这种调节可以预测 LBR 在人类口腔癌发生中的预防潜力。实验方法：IB-IIA 期术后临床试验将在 210 名 I 期或 II 期 HN 癌症手术切除后的个体中进行。每日 LBR 剂量（0、4、8 克）将通过两种给药系统给药，为期六个月。将在选定的时间点收集口腔刮屑、血液、尿液和唾液，并评估依从性/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果。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 成分的摄取之间的相互关系。目标 3. 评估 LBR 调节口腔癌术后高危口腔粘膜基因表达的能力。目标 4. 分析停止 LBR 治疗后调节基因的持续性。这项新颖的转化研究将为未来 III 期随机临床试验中纳入的实验和设计参数奠定科学基础，提供必要的数据，并且是第一个检查长期 LBR 给药对术后癌症患者高危口腔粘膜的分子影响的研究。它还将提供与可能导致口腔癌预防的关键基因调节相关的宝贵见解。 这项新颖的转化研究将为未来 III 期随机临床试验中纳入的实验和设计参数奠定科学基础，提供必要的数据，并且是第一个检查长期 LBR 给药对术后癌症患者高危口腔粘膜的分子影响的研究，并将提供与可能导致口腔癌预防的关键基因调节相关的宝贵见解。

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.