ORAL CANCER PREVENTION WITH MOLECULAR TARGETING THERAPY

通过分子靶向治疗预防口腔癌

• 批准号: 6989992
• 负责人: SCOTT M LIPPMAN
• 金额: $ 20.24万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6989992
• 关键词: biopsy; blood chemistry; cancer prevention; cancer risk; chemoprevention; clinical trial phase III; combination chemotherapy; drug screening /evaluation; early diagnosis; epidermal growth factor; genetic susceptibility; growth factor receptors; human subject; human therapy evaluation; international cooperation; kinase inhibitor; longitudinal human study; mouth neoplasms; neoplastic process; nonsteroidal antiinflammatory agent; oxidoreductase inhibitor; patient oriented research; pharmacogenetics; preneoplastic state; prostaglandin endoperoxide synthase; squamous cell carcinoma

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.

口腔癌是头颈部最常见的癌症，全球年发病率> 300，000，疾病和治疗相关的发病率高，生存率低，几十年来仅略有改善。寻找新的方法来控制这种疾病包括预防和早期发现，在口腔白斑，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发育不良和口腔癌的国家登记处， 口腔白斑癌序列的前瞻性研究。使用这些登记研究，我们能够研究该领域的几个关键问题，发现OPL切除术并不能降低癌症风险，COX 2表达与非整倍体密切相关，定期使用NSAID与头颈癌风险显著降低62%相关，这有力支持了靶向COX 2的药理学方法。我们发现DNA非整倍体是OPL患者癌症风险的最有力预测因子，预测3年癌症风险> 70%。非整倍体口腔癌 与预后不良有关。这些研究建立在MDACC和其他小组最近的分子风险结果的基础上，标志着克隆性和遗传不稳定性的分子标记物的到来，作为口腔白斑患者和多灶性疾病机制研究的标准风险评估工具。该提案是首个III期（癌症发病率）基于风险的OPL靶向管理，包括采用2X2安慰剂对照设计的COX 2抑制剂（塞来昔布）和EGFR/HER 2抑制剂（EKB-569）联合分子靶向治疗。我们假设EGFR/HER 2和COX 2信号通路在口腔中相互作用， 因此，研究人员发现，致癌作用促进遗传不稳定性和癌症发展，靶向抑制这些途径将预防或延迟口腔癌的发展。在本试验中靶向COX 2和EGFR的基本原理是，在头颈部癌发生中，两种靶向途径都被激活，临床前模型表明单一药物的抗肿瘤活性和联合药物的增强活性。此外，EGFR可以通过配体结合直接激活，也可以通过GPCR间接激活（PGE 2是GPCR配体）; EGFR/HER 2信号传导途径的下游介质可以诱导COX 2转录和PGE 2产生;因此，靶向COX 2和PGE 2都是EGFR/HER 2信号传导途径的靶点。 同时进行的途径可能更有效。