ORAL CANCER PREVENTION WITH MOLECULAR TARGETING THERAPY

口腔癌是最常见的头颈部癌症，全球年发病率为30万英镑，与疾病和治疗相关的发病率很高，存活率很低，几十年来只有轻微的改善。寻找控制这种疾病的新方法包括预防和早期发现口腔白斑，这是最常见的口腔癌前病变(OPL)。北欧癌症登记处是世界上唯一包括口腔异型增生和口腔癌的国家登记处，允许全面大规模 口腔白斑-癌序列的前瞻性研究。利用这些登记，我们能够研究这一领域的几个关键问题，发现OPL切除并不能降低癌症风险，COX2的表达与非整倍体密切相关，定期使用非类固醇抗炎药与头颈癌风险显著降低62%相关，这有力地支持了针对COX2的药理学方法。我们发现，DNA非整倍体是预测OPL患者癌症风险的最有力的指标，预测3年内癌症风险为70%。非整倍体口腔癌 与预后不良有关。这些研究建立在MDACC和其他组织最近的一系列分子风险结果的基础上，标志着克隆性和遗传不稳定性分子标记的到来，作为口腔白斑患者的标准风险评估工具，并用于研究多灶性疾病的机制。这项建议是OPLS的第一阶段-基于癌症发病率(癌症发病率)的靶向治疗，包括2X2安慰剂对照设计中COX2抑制剂(塞来昔布)和EGFR/HER2抑制剂(EKB-569)的联合分子靶向治疗。我们假设EGFR/HER2和COX2信号通路在口头上相互作用 有一种观点认为，癌症的发生可以促进遗传不稳定性和癌症的发展，而靶向抑制这些途径将防止或延缓口腔癌的发展。在这项试验中靶向COX2和EGFR的基本原理是，在头颈部癌变中，两个靶通路都被激活，临床前模型表明单一药物的抗肿瘤活性和组合的增强活性。此外，EGFR可以被配体结合直接激活，也可以被GPCRs间接激活(PGE2是一种GPCR配体)；EGFR/HER2信号通路的下游介体可以诱导COX2转录和PGE2产生；因此，两者都是靶向 事实证明，同时使用不同的途径可能会更有效。

Oral cancer is the most common cancer of the head and neck with a worldwide annual incidence of >300,000 and great disease- and treatment-related morbidity and poor survival, which has improved only marginally in decades. The search for new approaches to control this disease include prevention and early detection, within oral leukoplakia, the most common oral premalignant lesion (OPL). The Nordic cancer registries are the only national registries in the world that include oral dysplasia and oral cancer, allowing a comprehensive large scale prospective study the oral leukoplakia-cancer sequence. Using these registries we were able to study several key issues in this field and found that OPL resection does not reduce cancer risk, COX2 expression was tightly linked to aneuploidy and that regular NSAID use is associated with a striking 62% lower risk of head and neck cancer, strong support for a pharmacologic approach targeting COX2. We found that DNA aneuploidy was the most powerfull predictor of cancer risk in OPL patients, predicting a 3-year cancer risk of >70%. Aneuploid oral cancer is associated with a poor prognosis. These studies build on a recent body of molecular risk results from MDACC and other groups and mark the arrival of molecular markers of clonality and genetic instability as standard risk assessment tools for oral leukoplakia patients and for study of the mechanisms of multifocal disease. This proposal is the first phase-Ill (cancer incidence) risk-based targeted management of OPLs, including combination molecular targeted therapy with a COX2 inhibitor (celecoxib) and an EGFR/HER2 inhibitor (EKB-569) in a 2X2 placebo-controlled design. We hypothesize that EGFR/HER2 and COX2 signaling pathways interact in oral carcinogenesis to promote genetic instability and cancer development and that targeted inhibition of these pathways will prevent or delay oral cancer development. The rationale for targeting COX2 and EGFR in this trial is that in head and neck carcinogenesis both targets pathways are activated, and preclinical models indicate anti-tumor activity of the single agents and enhanced activity of the combination. Furthermore, EGFR can be activated directly by ligand binding and indirectly by GPCRs (PGE2 is a GPCR ligand); and downstream mediators of the EGFR/HER2 signaling pathway can induce COX2 transcription and PGE2 production; therefore targeting both pathways simultaneously may prove more efficacious.