Chinese Herbal Medicine as a Novel Paradigm for Cancer Chemotherapy

这是一份修订后的以临床和翻译为基础的跨学科项目资助申请，题为“中草药作为癌症化疗的新范式”。项目负责人为郑永智博士，主持项目二。他加入了另外两位知名的项目负责人，Edward Chu，医学博士（项目1），他也担任Co-P.l。赵宏宇博士（项目3）。这三个项目由行政核心（核心A）和分析核心（核心B）支持。在这个申请中，我们建议研究PHY906，一种在东方已经使用了近2000年的中草药。我们制定了严格的标准操作程序来生产cGMP材料，并开发了高灵敏度的化学（LC-MS）和生物（基因表达）指纹识别方法，以确保批量制备的质量控制和一致性。使用高质量的cGMP材料，我们计划进行一项随机、双盲、安慰剂对照研究，其中PHY906将与拓扑异构酶I抑制剂伊立替康（CPT-11）联合在二线mCRC患者中进行测试。在项目1中，朱博士将研究PHY906对CPT-11单药治疗的安全性、健康相关生活质量和临床疗效的影响。在项目2中，郑博士将进行一系列广泛的生物标志物分析，以确定潜在的药效学标志物，这些标志物可用于预测PHY906与CPT-11联合使用时的临床活性和疗效。在项目3中，赵博士将开发新的生物信息学和计算方法来挖掘来自项目2的转化数据，目的是确定与项目1中提出的研究确定的PHY906对CPT-11毒性的细胞保护作用和/或PHY906对CPT-11化疗临床疗效的调节作用相关的预测性生物标志物。建立了若干机制，以确保该计划的密切互动和凝聚力，其中包括项目领导人的月度会议、年度务静会和提供指导和建议的内部咨询委员会。

This is a revised clinical- and translational-based interdisciplinary Program Project Grant application entitled "Chinese Herbal Medicine as a Novel Paradigm for Cancer Chemotherapy". The Pl of this Program is Yung-chi Cheng, Ph.D., and he directs Project 2. He is joined two other well-established Project leaders, Edward Chu, M.D. (Project 1), who also serves as Co-P.l. of the Program, and Hongyu Zhao, Ph.D. (Project 3). These 3 Projects are supported by an Administrative Core (Core A) and an Analytical Core (Core B). In this application, we propose to investigate PHY906, a Chinese herbal medicine that has been used in the Orient for nearly 2000 years. Our group has developed a rigorous standard operating procedure to produce cGMP material as well as develop highly sensitive chemical (LC-MS) and biological (gene expression) fingerprinting methodologies to ensure quality control and consistency of batch preparation. Using high quality cGMP material, we plan to conduct a randomized, double-blind, placebo-controlled study where PHY906 will be tested in combination with the topoisomerase I inhibitor irinotecan (CPT-11) in patients with mCRC in the 2nd- line setting. In Project 1, Dr. Chu will investigate the effect of PHY906 on the safety, health-related quality of life, and clinical efficacy of CPT-11 monotherapy. In Project 2, Dr. Cheng will conduct an extensive series of biomarker analyses to identify the potential pharmacodynamic markers that can be used to predict for the clinical activity and efficacy of PHY906 when used in combination with CPT-11. In Project 3, Dr. Zhao will develop novel bioinformatic and computational methodologies to mine the translational data coming from Project 2 with the goal of identifying the predictive biomarkers that are associated with either the cytoprotective effects of PHY906 on CPT-11 toxicity and/or the modulatory effects of PHY906 on clinical efficacy of CPT-11 chemotherapy, as determined by the studies proposed in Project 1. Several mechanisms are in place to ensure the close interaction and cohesion of the Program, and these include monthly meetings of the Project leaders, an annual retreat, and an internal advisory board to provide guidance and advice.