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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA154295-03
Application #
8528511
Study Section
Special Emphasis Panel (ZCA1-GRB-S (M1))
Program Officer
Xi, Dan
Project Start
2011-09-15
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$1,214,842
Indirect Cost
$384,246
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Chen, Mengjie; Ren, Zhao; Zhao, Hongyu et al. (2016) Asymptotically Normal and Efficient Estimation of Covariate-Adjusted Gaussian Graphical Model. J Am Stat Assoc 111:394-406
Li, Cong; Yang, Can; Hather, Greg et al. (2016) Efficient Drug-Pathway Association Analysis via Integrative Penalized Matrix Decomposition. IEEE/ACM Trans Comput Biol Bioinform 13:531-40
Lin, Zhixiang; Li, Mingfeng; Sestan, Nenad et al. (2016) A Markov random field-based approach for joint estimation of differentially expressed genes in mouse transcriptome data. Stat Appl Genet Mol Biol 15:139-50
Zhu, Ruoqing; Zhao, Qing; Zhao, Hongyu et al. (2016) Integrating multidimensional omics data for cancer outcome. Biostatistics 17:605-18
Wang, Tao; Chen, Mengjie; Zhao, Hongyu (2016) Estimating DNA methylation levels by joint modeling of multiple methylation profiles from microarray data. Biometrics 72:354-63
Ryslik, Gregory A; Cheng, Yuwei; Modis, Yorgo et al. (2016) Leveraging protein quaternary structure to identify oncogenic driver mutations. BMC Bioinformatics 17:137
Huang, Xiu; Stern, David F; Zhao, Hongyu (2016) Transcriptional Profiles from Paired Normal Samples Offer Complementary Information on Cancer Patient Survival--Evidence from TCGA Pan-Cancer Data. Sci Rep 6:20567
Hu, Yiming; Zhao, Hongyu (2016) CCor: A whole genome network-based similarity measure between two genes. Biometrics 72:1216-1225
Wang, Ying; Lam, Wing; Chen, Shao-Ru et al. (2016) Tylophorine Analog DCB-3503 Inhibited Cyclin D1 Translation through Allosteric Regulation of Heat Shock Cognate Protein 70. Sci Rep 6:32832
Tsou, Lun K; Lara-Tejero, María; RoseFigura, Jordan et al. (2016) Antibacterial Flavonoids from Medicinal Plants Covalently Inactivate Type III Protein Secretion Substrates. J Am Chem Soc 138:2209-18

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