Inhibition of Oral Tumorigenesis by Antitumor B

抗肿瘤 B 抑制口腔肿瘤发生

• 批准号: 10516360
• 负责人: MING HU
• 金额: $ 47.14万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-08 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10516360
• 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; Chinese Herbs; 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; 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

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.

项目摘要： 抗肿瘤B（ATB），也称为Zeng Ping，是根据现代GMP标准制造的平板电脑。它 包含以下六种中国药​​用草药的摘录：sophora tonkinensis，polygonum bistorta，prunella 福尔加里斯，Sonchus Brachyotus，Dictamnus Dasycarpus和Dioscorea Bulbifera。以前，临床研究有 显示ATB对人类食管鳞状细胞癌的明显化学预防效率和 口服癌症。在口服白细胞病患者的随机临床试验中，用ATB治疗（4片，3次 每天持续8-12个月）减少了68％的患者口腔病变的大小，而在17％的患者中。 安慰剂对照组（p <0.01），表明ATB可能是反对开发的潜在预防剂 人类口腔癌。我们发现ATB抑制了化学诱导的口服鳞状细胞癌（通过 在小鼠中〜60％），并鉴定出能够抑制口腔癌细胞的几种关键活性化合物 增殖。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 并可能导致ATB的化学预防作用。但是，未知是否是关键的活动组件 （KAC），称为ATB-KACα，在三种活性化合物中富集50％或更多 Fraxinellone和Maackiain）因此，为QA/QC的目的更好地定义了化学定义，将具有强大的 对口服癌变的疗效比ATB。我们将同时使用4NQO诱导的口服癌变小鼠 模型和“机会窗口（WOO）”试验方法，以确定ATB-KACα的效率及其效率 药学（PD）反应和药代动力学（PK）特性和效率的生物标志物。我们 假设口服更好的化学定义ATB-KACα可以显着提高效率 防止小鼠模型中的口服癌变，并具有理想的PK特性和生物标志物 小鼠和人类的反应。 AIM 1将执行物理和药代动力学特征 ATB-KACα并开发PD/PK模型来描述其效率和生物标志物响应。 AIM 2将进行 小鼠口腔癌化学预防研究，以确定ATB-KACα对口服癌变和 识别新颖的生物标志物。 AIM 3将对新的患者进行ATB，ATB-KACα或安慰剂的WOO试验 诊断出口腔癌。该建议是及时且重要的，因为拟议的WOO试验是重要的一步 为了开发ATB-KACα，以填补未来人类II期研究 人类和匹配的小鼠模型中的生物标志物。此外，我们将测量PD和PK ATB-KACα在WOO试验中的响应并开发了PK/PD模型，以进一步增强我们的理解 未来的II期人类研究所需的必要剂量。

项目成果

Pharmacokinetic Characterization and Bioavailability Barrier for the Key Active Components of Botanical Drug Antitumor B (ATB) in Mice for Chemoprevention of Oral Cancer.

• DOI: 10.1021/acs.jnatprod.1c00501
• 发表时间: 2021-09-24
• 期刊: JOURNAL OF NATURAL PRODUCTS
• 影响因子: 5.1
• 作者: Bui, Dinh;Yin, Taijun;Duan, Shengnan;Wei, Bo;Yang, Peiying;Wong, Stuart J.;You, Ming;Singh, Rashim;Hu, Ming
• 通讯作者: Hu, Ming

Chemoprevention of Lung Cancer with a Combination of Mitochondria-Targeted Compounds.

• DOI: 10.3390/cancers14102538
• 发表时间: 2022-05-21
• 期刊: CANCERS
• 影响因子: 5.2
• 作者: Zhang, Qi;Xiong, Donghai;Pan, Jing;Wang, Yian;Hardy, Micael;Kalyanaraman, Balaraman;You, Ming
• 通讯作者: You, Ming

Mitochondria-targeted atovaquone promotes anti-lung cancer immunity by reshaping tumor microenvironment and enhancing energy metabolism of anti-tumor immune cells.

线粒体靶向的阿托伐醌通过重塑肿瘤微环境和增强抗肿瘤免疫细胞的能量代谢来促进抗肺癌免疫。

• DOI: 10.1002/cac2.12500
• 发表时间: 2024
• 期刊: Cancer communications (London, England)
• 作者: Xiong,Donghai;Yin,Zheng;Huang,Mofei;Wang,Yian;Hardy,Micael;Kalyanaraman,Balaraman;Wong,StephenT;You,Ming
• 通讯作者: You,Ming

Pharmacokinetic and Metabolic Profiling of Key Active Components of Dietary Supplement Magnolia officinalis Extract for Prevention against Oral Carcinoma.

• DOI: 10.1021/acs.jafc.0c01475
• 发表时间: 2020-06-17
• 期刊: Journal of agricultural and food chemistry
• 影响因子: 6.1
• 作者: Bui D;Li L;Yin T;Wang X;Gao S;You M;Singh R;Hu M
• 通讯作者: Hu M

Prevention of Tumor Growth and Dissemination by In Situ Vaccination with Mitochondria-Targeted Atovaquone.

• DOI: 10.1002/advs.202101267
• 发表时间: 2022-04
• 期刊: ADVANCED SCIENCE
• 影响因子: 15.1
• 作者: Huang, Mofei;Xiong, Donghai;Pan, Jing;Zhang, Qi;Wang, Yian;Myers, Charles R.;Johnson, Bryon D.;Hardy, Micael;Kalyanaraman, Balaraman;You, Ming
• 通讯作者: You, Ming