Inhibition of Oral Tumorigenesis by Antitumor B

抗肿瘤 B 抑制口腔肿瘤发生

基本信息

批准号：
10170283
负责人：
MING HU
金额：
$ 40.35万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-08 至 2021-05-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10170283
关键词：
A/J Mouse Aftercare Animal Model Antitumor Response Area Biological Biological Availability Biological Markers Blood Circulation Cancer Model Cell Proliferation Chemicals Chemoprevention Chemopreventive Agent Chinese Herbs Chinese People Clinical Clinical Research Clinical Trials Control Groups Development Dictamnus Dose Drug Kinetics Esophageal Squamous Cell Carcinoma Exposure to Future Goals Human In Vitro Incidence Knowledge Lesion Malignant neoplasm of esophagus Measures Medicinal Herbs Modernization Molecular Target Mouth Neoplasms Mus Newly Diagnosed Normal tissue morphology Oral Oral Administration Oral Leukoplakia Pathway interactions Patients Pharmacodynamics Phase Phase II Clinical Trials Phytochemical Placebo Control Placebos Plasma Polygonum Prevention trial Preventive Property Protocols documentation Prunella vulgaris Publishing Randomized Randomized Clinical Trials Research Project Grants Resected Saliva Sampling Sonchus Sophora Tablets Testing Time Tissues Transgenic Organisms United States Yam - dietary antitumor effect arm base cancer chemoprevention cohort design in vivo inhibitor/antagonist insight liquid chromatography mass spectrometry malignant mouth neoplasm molecular marker mouse model mouth squamous cell carcinoma neoplastic cell novel marker oral carcinogenesis oral lesion oral tissue oral tumorigenesis patient population pharmacodynamic model pharmacokinetic model pharmacokinetics and pharmacodynamics phase 2 study pre-clinical predictive marker prevent response response biomarker transcriptome sequencing tumor

项目摘要

Project Summary: Antitumor B (ATB), also known as Zeng Sheng Ping, is a tablet made according to modern GMP standards. It contains the extracts of following six Chinese medicinal herbs: Sophora tonkinensis, Polygonum bistorta, Prunella vulgaris, Sonchus brachyotus, Dictamnus dasycarpus, and Dioscorea bulbifera. Previously, clinical studies have shown significant chemopreventive efficacy of ATB against human esophageal squamous cell carcinomas and oral cancers. In a randomized clinical trial in patients with oral leukoplakia, treatment with ATB (4 tablets, 3 times per day for 8–12 months) reduced the size of oral lesions in 68% of the patients versus 17% of the patients in the placebo control group (P < 0.01), indicating that ATB may be a potent preventive agent against the development of oral cancer in humans. We found that ATB inhibited chemically induced oral squamous cell carcinomas (by ~60%) in mice and identified several key active compounds that are capable of inhibiting oral cancer cell proliferation. Our published study also showed that several key active compounds were found in the oral tissues and likely contributed to the chemoprevention effects of ATB. However, it is unknown if a key active component (KAC), called ATB-KACα which is enriched with 50% or more of three active compounds (i.e., dictamine, fraxinellone and maackiain) and therefore better chemically defined for QA/QC purposes, will have a stronger efficacy against oral carcinogenesis than ATB. We will use both the 4NQO-induced oral carcinogenesis mouse model and a “window of opportunity (WOO)” trial approach to determine the efficacy of ATB-KACα along with its pharmacodynamic (PD) responses and pharmacokinetic (PK) properties and biomarkers of efficacy. We hypothesize that oral administration of a better chemically defined ATB-KACα can significantly increase efficacy in preventing oral carcinogenesis in mouse models and will have the desirable PK properties and biomarker responses in both mice and humans. Aim 1 will perform phytochemical and pharmacokinetic characterizations of ATB-KACα and develop a PD/PK model to describe their efficacy and biomarker responses. Aim 2 will conduct mouse oral cancer chemoprevention studies to determine the efficacy of ATB-KACα on oral carcinogenesis and to identify novel biomarkers. Aim 3 will perform a WOO trial of ATB, ATB-KACα, or placebo in patients with newly diagnosed oral cancer. This proposal is timely and significant because the proposed WOO trial is important step for the development of ATB-KACα for future human phase II studies by filling the knowledge gap between biomarkers in humans and those in the matched mouse models. In addition, we will measure the PD and PK responses of ATB-KACα in the WOO trial and develop a PK/PD model to further enhance our understanding the necessary dose needed for future phase II human studies.

项目概要：抗肿瘤B（ATB）又名增生平，是按照现代GMP标准生产的片剂。含有以下六种中药材的提取物：山豆根、蓼、夏枯草此前已有临床研究表明，白芫荽、白芫荽、黄芩等。显示 ATB 对人食管鳞状细胞癌具有显着的化学预防功效在一项针对口腔白斑患者的随机临床试验中，使用 ATB 治疗（4 片，3 次）每天一次，持续 8-12 个月）减少了 68% 患者的口腔病变大小，而对照组中这一比例为 17% 安慰剂对照组（P < 0.01），表明 ATB 可能是一种有效的预防药物我们发现 ATB 可以抑制化学诱导的口腔鳞状细胞癌（通过 ~60%）在小鼠中，并鉴定出几种能够抑制口腔癌细胞的关键活性化合物我们发表的研究还表明，在口腔组织中发现了几种关键的活性化合物。并可能有助于 ATB 的化学预防作用，但尚不清楚是否是关键活性成分。 (KAC)，称为 ATB-KACα，富含 50% 或更多的三种活性化合物（即白客明、 fraxinellone 和 maackiain），因此为 QA/QC 目的进行更好的化学定义，将具有更强的对抗口腔癌的功效优于 ATB 我们将使用 4NQO 诱导口腔癌的小鼠。模型和“机会之窗（WOO）”试验方法来确定 ATB-KACα 的功效及其药效（PD）反应和药代动力学（PK）特性以及功效的生物标志物。研究表明，口服化学成分更好的 ATB-KACα 可以显着提高治疗效果在小鼠模型中预防口腔癌发生，并具有理想的 PK 特性和生物标志物目标 1 将进行植物化学和药代动力学表征。 ATB-KACα 并开发 PD/PK 模型来描述其功效和生物标志物反应，目标 2 将进行。小鼠口腔癌化学预防研究，以确定 ATB-KACα 对口腔癌发生和预防的功效为了识别新的生物标志物，Aim 3 将在新发患者中进行 ATB、ATB-KACα 或安慰剂的 WOO 试验。该提案是及时且重要的，因为拟议的 WOO 试验是重要的一步。通过填补之间的知识空白，开发用于未来人类 II 期研究的 ATB-KACα 此外，我们还将测量人类和匹配小鼠模型中的生物标志物。 ATB-KACα 在 WOO 试验中的反应并开发 PK/PD 模型以进一步增强我们的理解未来第二阶段人体研究所需的必要剂量。