Molecular-Based Therapy for Oral Cancer Prevention

描述(申请人提供)：全球每年新增病例30万例，发病率高，存活率低，口腔癌需要新的治疗方法，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。P01是一项针对全球口腔癌威胁的国际协同合作，结合了丰富的患者基础、用于人口研究的新型肿瘤登记和来自北欧地区的研究人员的临床、病理和生物学专业知识、翻译预防方面的专业知识(包括癌症发生和遗传易感性的分子研究、多个生物标志物的统计分析和药理学)，以及康奈尔大学的合作者在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信号通路的生物学以及针对这些通路的药物在口腔癌发生中的影响，并阐明针对COX-2、EGFR和HER2的预防性干预的口腔癌前病变(OPL)高危患者的分子生物学和风险以及药物基因组学特征，这三个靶点在FDA批准的分子靶向药物的肿瘤形成中得到验证。为了实现这些目标，我们建议进行一项整合分子研究的第三阶段随机对照试验(RCT)。项目1(分子靶向治疗预防口腔癌)是一项以人群为基础的随机对照试验，采用2×2析因设计，在患有非整倍体口腔癌的极高风险患者中测试塞来昔布和EKB-569，这些患者3年内发生侵袭性口腔癌的风险为70%。干预的基本原理包括，在口腔癌发生过程中，两个靶点/通路都被激活，临床前模型表明单一药物的抗肿瘤活性和联合药物的增强活性。项目2-4与区域合作研究密切相关。项目2：针对口腔癌变中的COX-2和EGFR信号转导；项目3：口腔癌变中的分子缺陷；项目4：口腔癌变中的分子流行病学和药物遗传学。还包括核心(行政、生物统计/数据管理和生物化学、病理学、药理学)，以提供成功整合和执行这些研究所需的结构和专业知识。在这个项目中获得的对口腔癌的新的临床和机制洞察将与其他肿瘤类型高度相关，例如结直肠癌。

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.