MOLECULAR DEFECTS IN ORAL CARCINOGENESIS

口腔癌是头颈部最常见的肿瘤，全世界每年的发病率估计超过30万。口腔白斑是一种癌前病变，在口腔中发生癌症的风险增加，因此是预防研究的极佳模型。我们已经证明，许多口腔白斑是遗传性病变，具有更高的癌症进展风险。化学预防策略已被证明是预防或延缓高危人群癌症发展的有力工具。然而，必须开发中间终点来确定化学预防药物的有效性，以缩短临床试验持续时间并节省资源。我们假设分子的改变在 口腔肿瘤的早期发生可以作为准确预测口腔癌发生风险的生物标志物，而通过化学预防药物消除或减少这种改变可以预防或延缓口腔癌的发展。我们进一步假设，分子谱和对化学预防药物(S)的反应预测了个体对化学预防药物(S)的生物学疗效，从而预测了预防策略的结果。为了验证这些假说，我们计划(1)在口腔癌前病变(OPL)患者中确定关键抑癌基因杂合性缺失(LOH)在预测口腔癌风险中的作用。我们将决定 DNA含量状态的杂合性缺失在评估口腔癌风险中的附加值。(2)确定关键抑癌基因启动子异常甲基化单独或与杂合性缺失(LOH)联合应用在预测口腔鳞癌患者口腔癌风险中的作用。(3)探讨环氧合酶-2(COX-2)抑制剂和表皮生长因子受体(EGFR)抑制剂单独或联合应用是否能减少口腔癌基因启动子异常甲基化的细胞群，从而降低口腔癌的发病率。(4)确定OPL与口腔癌/OPL的克隆关系，以了解化学预防药物的治疗作用。(5)利用蛋白质组学方法寻找在癌症风险评估中重要的新生物标志物，并揭示体内化学预防药物的新机制。的成功之路 该项目将建立一个经过验证的生物标记物小组，用作口腔癌风险的预测因子和化学预防试验的中间替代品。新的生物标志物和使用的预防性药物的体内机制也将被发现。

Oral cancer is the most common neoplasm of the head and neck with an estimated annual incidence over 300,000 worldwide. Oral leukoplakia is a precancerous lesion with an increased risk of cancer development in oral cavity and therefore, an excellent model for prevention studies. We have shown that many oral leukoplakia are genetic lesions which carry higher risk to progress to cancer. Chemoprevention strategy has proved to be a powerful tool to prevent or delay cancer development in high risk populations. However, intermediate endpoints must be developed to determine efficacy of chemopreventive agents in order to shorten the duration of clinical trials and save resources. We hypothesize that molecular alterations critical in early oral tumorigenesis can serve as biomarkers to accurately predict the risk of oral cancer development and elimination or reduction of such alterations by chemopreventive agents can prevent or delay oral cancer development. We further hypothesize that molecular profiles and responses to chemopreventive agent(s) predict individual's biological efficacy of the agent(s) and therefore, outcomes of the preventive strategy. To test these hypotheses, we plan (1) To determine loss of heterozygosity (LOH) at critical tumor suppressor loci in predicting oral cancer risk prospectively in patients with oral premalignant lesions (OPL). We will determine an added value of LOH to DNA content status in assessing oral cancer risk. (2) To determine the role of aberrant promoter methylation at critical tumor suppressor genes alone or in combination with LOH in predicting oral cancer risk prospectively in patients with OPL. (3) To determine whether COX-2 inhibitor and epidermal growth factor receptor (EGFR) inhibitor alone or in combination can reduce the cell populations with aberrant promoter methylation and therefore reduce oral cancer rate. (4) To determine clonal relationship between OPL and subsequently developed oral cancer/OPL to understand therapeutic role of the chemopreventive agents. (5) To identify novel biomarkers important in cancer risk assessment and reveal novel mechanisms of the chemopreventive agents in vivo using proteomic approaches. The success of the project will establish a panel of validated biomarkers to be used as predictors for oral cancer risk and intermediate surrogates for chemoprevention trials. Novel biomarkers and in vivo mechanisms of the preventive agents used will also be discovered.