Molecular-Based Therapy for Oral Cancer Prevention

口腔癌简介（申请人提供）：口腔癌全球每年新增病例30万例，发病率高，生存率低，需要新的治疗方法，包括预防和早期发现。化学预防是一种很有前途的方法，已经显示出控制乳腺癌、结肠癌和前列腺癌的潜力。该P01是针对口腔癌全球威胁的国际协同合作，结合了丰富的患者基础、基于人群研究的新型肿瘤登记、北欧地区研究人员的临床、病理和生物学专业知识、转化预防方面的专业知识，包括致癌作用和遗传易感性的分子研究、多种生物标志物的统计分析和药理学。安德森癌症中心头颈癌研究团队的成员，以及康奈尔大学合作者在COX2和EGFR/HER2信号通路方面的深厚专业知识。我们项目的总体目标是帮助控制口腔癌的发病率，阐明COX-2和EGFR/HER2信号通路的生物学特性，以及靶向这些途径的药物对口腔癌发生的影响，阐明口腔癌的分子生物学和风险，以及针对COX-2、EGFR和HER2的预防性干预的高危口腔癌前病变（OPL）患者的药物基因组学特征。FDA批准的分子靶向药物在肿瘤中验证了所有3个靶点。为了实现这些目标，我们建议开展一项整合分子研究的iii期随机对照试验（RCT）。项目1（口腔癌预防与分子靶向治疗）是一项基于人群的随机对照试验，在非整倍体口腔癌患者中进行2 × 2因子设计，测试塞来昔布和EKB-569，这些患者3年发展为生物侵袭性口腔癌的风险为70%。干预的基本原理包括这样一个事实，即在口腔癌发生中，两个靶点/途径都被激活，临床前模型表明单一药物的抗肿瘤活性和联合药物的活性增强。项目2-4与随机对照试验密切相关。项目二：靶向COX-2和EGFR信号在口腔癌变中的作用；项目三：口腔癌变中的分子缺陷；项目四：口腔癌变的分子流行病学和药物遗传学。核心（行政管理、生物统计学/数据管理、生物标本、病理学、药理学）也包括在内，以提供成功整合和执行这些研究所需的结构和专业知识。在该项目中获得的口腔癌的新临床和机制见解将与其他肿瘤类型（如结直肠癌）高度相关。

DESCRIPTION (provided by applicant): With 300,000 yearly new cases worldwide, profound morbidity, and poor survival, oral cancer needs new treatment approaches, including prevention and early detection. Chemoprevention is a promising approach already showing potential for controlling breast, colon and prostate cancer. This P01 is an international, synergistic collaboration against the global threat of oral cancer, combining the rich patient base, novel tumor registry for population-based study and clinical, pathologic and biologic expertise of investigators from the Nordic region, the expertise in translational prevention, including molecular study of carcinogenesis and genetic susceptibility, statistical analyses of multiple biomarkers, and pharmacology, of the head and neck cancer research team at M. D. Anderson Cancer Center, and the profound expertise in COX2 and EGFR/HER2 signaling pathways by collaborators at Cornell University. The overall objectives of our program project are to help control the incidence of oral cancer, elucidate the biology of COX-2 and EGFR/HER2 signaling in and the impact of agents targeting these pathways on oral carcinogenesis, and elucidate the molecular biology and risk of oral cancer and the pharmacogenomic profiles of high-risk oral premalignant lesion (OPL) patients with respect to preventive interventions directed at COX-2, EGFR and HER2, all 3 targets validated in neoplasia with FDA approved molecular targeting drugs. To accomplish these goals we propose to carry out a phase-III randomized controlled trial (RCT) integrating molecular studies. Project 1 (Oral Cancer Prevention with Molecular Targeting Therapy) is a population-based RCT testing Celecoxib and EKB-569 in a 2 X 2 factorial design in extremely high-risk patients with aneuploid OPLs who have a >70% 3-year risk of developing biologically aggressive oral cancer. The rationale for the intervention includes the fact that in oral carcinogenesis both targets/pathways are activated, and preclinical models indicate anti-tumor activity of the single agents and enhanced activity of the combination. Projects 2-4 are tightly linked to the RCT. Project 2: Targeting COX-2 and EGFR Signaling in Oral Carcinogenesis; Project 3: Molecular Defects in Oral Carcinogenesis; Project 4: Molecular Epidemiology and Pharmacogenetics in Oral Carcinogenesis. The Cores (Administration, Biostatistics/Data Management, and Biospecimen, Pathology, Pharmacology) are also included to provide the structure and expertise required for the successful integration and execution of these studies. The new clinical and mechanistic insights into oral cancer gained in this program will be highly relevant to other tumor types, such as colorectal cancer.