DEVELOPMENT OF NOVEL CURCUMIN ANALOGS FOR THE TREATMENT OF HEAD AND NECK CANCER

开发用于治疗头颈癌的新型姜黄素类似物

• 批准号: 8282823
• 负责人: HAIAN FU
• 金额: $ 33.27万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8282823
• 关键词: Affinity Chromatography; Animal Model; Antineoplastic Agents; Apoptosis; Biochemical; Biological; Biological Availability; Biological Factors; Biological Markers; Biological Models; Cancer cell line; Cell Culture System; Clinic; Clinical; Clinical Data; Clinical Trials; Computer Assisted; Curcumin; Development; Disease; Dose; Drug Kinetics; Effectiveness; Future; Generations; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human; In Vitro; Investigation; Lead; Liquid substance; Mediating; Metabolism; Modification; Molecular; Molecular Target; Monitor; NF-kappa B; Nature; No-Observed-Adverse-Effect Level; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology and Toxicology; Phase; Preventive; Property; Radiation therapy; Recommendation; Recurrence; Recurrent disease; Refractory; Reproduction spores; Research Personnel; Rodent; Safety; Solid; Solid Neoplasm; Source; Specificity; Survival Rate; Synthesis Chemistry; Taxane Compound; Testing; Therapeutic; Thromboplastin; Toxicology; Treatment Efficacy; Tumor Angiogenesis; Unresectable; Vascular Endothelial Growth Factors; Water; Xenograft Model; Xenograft procedure; advanced disease; analog; base; cancer cell; chemotherapy; cytotoxic; disorder control; docetaxel; drug discovery; exhaust; head and neck cancer patient; improved; in vivo; in vivo Model; multidisciplinary; next generation; novel; novel therapeutics; positional cloning; pre-clinical; programs; research clinical testing; response; standard care; taxane; therapeutic development; treatment strategy; tumor; tumor xenograft

Project 3 aims to develop novel curcumin analogs for the treatment of head and neck cancer. Despite advances in targeted therapies in recent years, the long term disease-free and overall survival rates for patients with advanced disease remain poor, and treatment options for recurrent disease are very limited. However, recent advances in our understanding of the molecular basis of head and neck cancer have presented new opportunities for novel therapeutic development. The long-term goal of this application is to develop a new generation of anticancer agents that target critical survival pathways in head and neck cancers. Nature represents a rich source for drug discovery, and our strategy is to start with a safe natural product with a promising activity, such as curcumin. The demonstrated preventive and therapeutic potential of curcumin together with its attractive safety profile begs for immediate efforts to develop curcumin-based agents with improved bioavailability and enhanced anticancer efficacy. In an attempt to retain curcumin's safety profile, while increasing its potency, our preliminary studies have produced a lead compound, EF24. EF24 potently induces apoptosis of various cancer cells, inhibits tumor angiogenesis activity, and decreases tumor size in an animal model. Mechanistic studies have pointed to the NF-kB pathway as a critical molecular target for its potential therapeutic efficacy. To provide alternative candidates, the closely related analog EF31 and their water soluble analogs were synthesized and show promising biological properties. Based on these exciting findings, we propose to rapidly move these curcumin analogs into the clinic. Our study aims to (i) define the mechanism of action of EF24 and its analogs using in vitro and in vivo models, (ii) identify molecular biomarkers that response to the treatment with these drugs, (iii) determine pharmacology and toxicology profiles of these compounds to predict a NOAEL dose in humans, and (iv) select the most promising compounds for clinical evaluation in a phase 0 trial in head and neck cancer patients. Thus, our primary aim is to understand the mechanism of action of novel curcumin analogs, to define their pharmacology and toxicology profiles, and to initiate clinical testing of this new generation of anticancer agents with the ultimate goal of improving treatment options for head and neck cancer patients.

项目3旨在开发用于治疗头颈癌的新型姜黄素类似物。尽管 近年来，有针对性疗法的进步，长期无病和总生存率 患有晚期疾病的患者仍然很差，并且复发性疾病的治疗选择非常有限。 但是，我们对头颈癌分子基础的理解的最新进展已有 为新的治疗发展提供了新的机会。该应用程序的长期目标是 开发新一代的抗癌药，以靶向头颈部关键生存途径 癌症。大自然代表了毒品发现的丰富来源，我们的策略是从安全的自然开始 具有有希望的活性的产品，例如姜黄素。展示的预防和治疗潜力 姜黄素以及其吸引人的安全性概况乞求立即努力开发基于姜黄素的 具有提高生物利用度和增强抗癌功​​效的药物。试图保留姜黄素 安全性概况在提高其效力的同时，我们的初步研究产生了铅化合物EF24。 EF24有效诱导各种癌细胞的凋亡，抑制肿瘤血管生成活性，并降低 动物模型中的肿瘤大小。机械研究已指出NF-KB途径是关键的 其潜在治疗功效的分子靶标。为了提供替代候选人，密切相关 类似于EF31及其水溶性类似物是合成的，并显示出有希望的生物学特性。 根据这些令人兴奋的发现，我们建议将这些姜黄素类似物迅速移至诊所。我们的 研究旨在（i）使用体外和体内模型定义EF24及其类似物的作用机理，（ii） 确定对这些药物治疗反应的分子生物标志物（iii）确定药理学 这些化合物的毒理学概况，以预测人类的Noael剂量，并且（iv）选择最多 在头颈癌患者中，在0期试验中进行临床评估的有希望的化合物。 因此，我们的主要目的是了解新型姜黄素类似物的作用机理，以定义其 药理学和毒理学概况，并启动这种新一代抗癌的临床测试 具有改善头颈癌患者治疗选择的最终目标的代理。