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.

Public Health Relevance

This is a multi-investigator, clinical- and translational-based grant that seeks to investigate the role of a novel Chinese herbal medicine as a modulator of cancer chemotherapy in the treatment of metastatic colorectal cancer. This study may serve as a new treatment paradigm for developing herbal and/or botanical medicines in combination with cancer chemotherapy for the treatment of other human cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-GRB-S (M1))
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Xi, Dan
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Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
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Ryslik, Gregory A; Cheng, Yuwei; Cheung, Kei-Hoi et al. (2014) A graph theoretic approach to utilizing protein structure to identify non-random somatic mutations. BMC Bioinformatics 15:86
Hou, Lin; Chen, Min; Zhang, Clarence K et al. (2014) Guilt by rewiring: gene prioritization through network rewiring in genome wide association studies. Hum Mol Genet 23:2780-90
Ryslik, Gregory A; Cheng, Yuwei; Cheung, Kei-Hoi et al. (2014) A spatial simulation approach to account for protein structure when identifying non-random somatic mutations. BMC Bioinformatics 15:231
Saif, Muhammad Wasif; Li, Jia; Lamb, Lynne et al. (2014) First-in-human phase II trial of the botanical formulation PHY906 with capecitabine as second-line therapy in patients with advanced pancreatic cancer. Cancer Chemother Pharmacol 73:373-80
Chen, Xiaowei; Slack, Frank J; Zhao, Hongyu (2013) Joint analysis of expression profiles from multiple cancers improves the identification of microRNA-gene interactions. Bioinformatics 29:2137-45
Ryslik, Gregory A; Cheng, Yuwei; Cheung, Kei-Hoi et al. (2013) Utilizing protein structure to identify non-random somatic mutations. BMC Bioinformatics 14:190
Rockwell, Sara; Grove, Tina A; Liu, Yanfeng et al. (2013) Preclinical studies of the Chinese Herbal Medicine formulation PHY906 (KD018) as a potential adjunct to radiation therapy. Int J Radiat Biol 89:16-25
Liu, Shwu-Huey; Cheng, Yung-Chi (2012) Old formula, new Rx: the journey of PHY906 as cancer adjuvant therapy. J Ethnopharmacol 140:614-23