1. Introduction

    This project combines the leading cancer research teams of NTUCM and CMU&H, to achieve the goal of 'establishing a top cancer research center in the world'. As the current 'Top International Research Center' proposed by NTUCM, CMU&H and MD Anderson already has a strong basic research foundation, the main objective of this center is to apply and translate basic research into new drug development and new diagnostic techniques. This center will have a great potential to become a top cancer research center in Asia. One research direction for "bench to bedside", is to explore the molecular mechanisms of cancer; the research fields include genomics, metabolomics, signal transduction pathway, drug design and screening, animal models for anti-cancer drug, molecular epidemiology and stem cells. While another research direction for "bedside to bench" will be to address the problems encountered during clinical treatment of cancer patients, such as drug resistance, cancer metastasis, cancer recurrence, serious complications resulted from treatment etc, in order to develop personalized medicine and executed by the 'Cancer Research Center of Excellence' of both CMU&H and NTUCM. Finally, the 'National Clinical Trial and Research Center' (NCTRC) will implement a phase I clinical trial to examine the results of cancer translational research. In addition, the cross-country clinical trials will be capable to solve the cell signaling pathways targeted by potential drugs and therapies. Please see the following figure for the workflow of the integrated cancer translational research.
 
research frame
 

2. Functional genomic research

    The 'NTU Center for Genomic Medicine' has cutting-edge facilities that provide a platform for high throughput genomic and proteomic research, including chromosomal DNA variations (single nucleotide polymorphism, DNA insertion or deletion, single mutations and gene copy number variations), epigenetic regulation of chromosome (DNA methylation and complex of chromosomal DNA and histone), gene expression analysis (whole genome expression profile, microarray-based gene expression profiling and quantification of gene or microRNA expression), analysis of protein expression (cytokine expression profiles and protein and DNA interactions), metabolomic analysis (qualitative and quantitative analyses of small molecules and small volatile molecules), characterization of cancer cells (cancer cell migration and invasion, cancer cell regeneration, angiogenesis), high-throughput cell imaging and drug screening platform and integrated microarray databases and bioinformatic analysis platform.
 

3. Cancer stem cell research

    The Stem Cell Core Laboratory of the 'NTU Center for Genomic Medicine' has established a stem cell sorter platform. The stem cell research team led by Professor Min-Liang Kuo focuses on cancer stem cells isolated from colorectal cancer and lung cancer using the metabolomic and genomic techniques to identify potential tumor markers or biomarkers. On the other hand, Professor Mien-Chie Hung's stem cell research team in CMU&H investigates critical signaling pathways and molecular mechanisms that are involved in the expansion of cancer stem cells. Success of this project will foster the development of novel cell-based therapies for human diseases including cancer. The collaboration on the cancer stem cell research between CMU&H and MD Anderson has already resulted six papers published in Cancer Cell, Nature Cell Biology and Journal of Biological Chemistry in 2011. By this Top International Research Center project, it is expected that CMU&H and NTUCM collaborated with the cancer stem cell research team of MD Anderson will have a further breakthrough of these important molecules in the clinical outcome and their regulatory mechanism and the interactions between metabolites and microRNAs. Using this international research center and clinical trial platform, the stem cell research of NTU and CMU&H has great potential to one of the top stem cell programs in the world.
 

4. Novel anti-cancer compound development and translational research: Basic research for mechanism of carcinogenesis, establishment of animal models for anti-cancer drug development and enhancement translational medical research

    In order to promote translational medical research, the cancer biology research in CMU, assisted by a number of well-known researchers of MD Anderson Cancer Center including Dr. Mien-Chie Hung, not only does established the first 'Graduate Institute of Cancer Biology' in Taiwan, and set up a joint course with Academia Sinica, 'The Ph.D. Program for Cancer Biology and Drug Discovery', but CMUH also established Center for Molecular Medicine (CMM), which emphasizes the study of epigenetics/epigenomics, molecular signaling pathways, and the microenvironment of cancer cells and cancer stem cells. These factors play significant roles in the formation, proliferation, propagation, local tissue invasion and migration of cancer and thus are the main topics of basic research for the international cancer research center. The laboratories of CMM are housed with state-of-the-art equipment and facilities such as animal facilities to conduct experiments proposed in the current proposal. In just five years, CMM has published many papers with MD Anderson Cancer Center in the top international journals, such as Nature, Cell, Cancer Cell, Nature Cell Biology and Molecular Cell. In addition, we plan to push the novel treatment strategies, such as Endostatin-Cytosine deaminase (Endo-CD) and VISA-BikDD, into clinical trials. VISA is a powerful gene expression platform that delivers anti-tumor genes into specific tumors. The therapeutic effect of BikDD gene therapy driven by VISA was confirmed in pancreatic animal models as well as other cancer models, and published in Cancer Cell (12:52-65, 2007), Oncogene (28:3286-3295, 2009), Molecular Cancer Therapeutics (8:2375-2382, 2009), Oncogene (30:1773-1783, 2011), and Molecular Cancer Therapeutics (10:637-647, 2011). More recently, in a breast cancer model, VISA-BikDD was found to effectively inhibit the growth of breast cancer stem cells and this paper has been in press by Cancer Cell. Endo-CD is a novel dual-targeting anti-angiogenesis therapy, (proof of concept is published in Cancer Research, 66:378-384, 2006), that we found to be at least as effective against cancer cells as and less cytotoxic to normal cells than the antiangiogenic drug Avastin (bevacizumab), which was approved by the FDA in several cancer types, though recently the FDA recommended to revoke its approval in breast cancer. TTY Biopharm has expressed interest in licensing and developing Endo-CD and VISA-BikDD from MD Anderson. Negotiations for the agreement are currently ongoing. If this deal is successful, as expected, this will be great example for transforming basic research into drug discovery and clinical trials.
 

5. Core technology of research

    The platform of genomic research: Microarray Core Laboratory of NTU Center of Genomic Medicine is one of the central platforms for functional genomics and translational research in the genomic era and uses gene chips from Illumina, Affymetrix, Agilent and Roche for the detection of single nucleotide polymorphism, gene copy number, gene expression, microRNA expression and DNA methylation. DNA mass spectrometer is able to quantify DNA insertion, deletion, single mutation and DNA methylation. Also, this core laboratory has a new generation sequencing system with maximum capacity in Taiwan including four ABI SOLiD4 and one Illumina GAIIX, and will set up three ABI 5500 this year. As a result, the core laboratory will be one of top five gene sequencing centers in Asia.
 
    The platform of metabolomic research: Metabolomic Core Laboratory, NTU Center of Genomic Medicine can provide the following services: Sample preparation and storage (blood, urine and tissue), sample analyses (UHPLC/Q-TOF: qualitative analysis of small molecules, UHPLC/MS-MS (QQQ): quantification of small molecules, 2D-GCxGC/TOF: qualitative analysis of small gas molecules and GC/MS (Quadrupole): quantitative analysis of small gas molecules) and the metabolomic bioinformatic analysis.
 
    The platform of proteomic research:CMU has built 'Proteomics Research Core Laboratory', which can be widely applied in many researches and developments, including: (1) Systematic identification of proteins and their post-translational modification to establish the disease-specific proteomic database. (2) Comparative analyses of protein changes in different environmental conditions or stimuli (e.g. diseases, differentiation and drug treatments etc.) in order to search for possible mechanisms of regulation, and thus to develop new drugs. (3) To study protein-protein interaction through the recognition of protein complexes, in order to clarify the function of unknown proteins. At present, the core laboratory has the following equipments: MALDI-TOF/TOF (Bruker Daltonics UltraFlex III) and LC-MS/MS, Ultra High Capacity Trap Mass Spectrometry (HCTultra) (LC: Dionex; MS: Bruker Daltonics).
 
    The platform of stem cell research: Stem Cell Core Laboratory of NTU Center of Genomic Medicine has a BD FACSAria cell sorting system for sorting stem cell, a Leica TCS-SP5 confocal microscope for identification of cancer stem cells, a LEAP – stem cell manager, which applies laser dissection techniques for large scale production of homogeneous stem cell cultures, and a Xenogen IVIS imaging system for in vivo detection of fluorescent or phosphorescent markers of cancer stem cells in mice, evaluation of the efficacy of novel anti-cancer drugs against tumor cells and investigation of the roles of the tumor suppressors or oncogenes in tumor formation, angiogenesis and metastasis.
 
    The platform of primary cancer cell culture and drug screening: NTU Center of Genomic Medicine cultured a variety of primary cell lines with drug resistance from the tissue or malignant pleural effusion of cancer patients. These cell lines are excellent tools for studying the relationships among the various types of gene mutation, tumor metastasis, the mechanisms drug resistance and the characteristics of stemness. In addition, the center has established a high content screening system for drug screening and quantitative and qualitative analyses of cancer cells.
 
    Cancer mouse model: NTU Center of Genomic Medicine has established two types of cancer mouse models: (1) Inoculation of human cancer cells into immunodeficient mice as a model for analyses of in vivo tumor formation, angiogenesis and metastasis and (2) inoculation of human cancer cells into EGFR transgenic mice for optimizing the formation of lung cancer in mice. So far, a cytopathic effect can be observed two weeks after inoculation and after four weeks lung tumors can be formed. This transgenic mouse model is good for the study of EGRF mutation, the relationship of stroma micro-environment and lung cancer formation and drug preclinical trials.
 
   The platform of animal models for anti-cancer drug development and novel signaling pathway research: CMM, CMUH has established a variety of animal models to study novel signaling pathway networks in vivo, which provides a platform for the preclinical assessment of drug efficacy and animal toxicity tests. The aim is to develop new drugs for targeted therapy and discover molecular markers for the development of personalized medicine.
 
   The platform of anti-cancer natural compound screening: Using the natural compound database, we will screen the natural products against specific targets, such as enzymes, receptors and proteins etc and so this becomes the basis for future drug development. In order to develop various anti-cancer drugs, this platform utilizes cell-based and target-based screening as a basis, supplemented by computer-aided drug design (CADD) combing the fields of physical chemistry and bioinformatics. Applying the new high-speed computing drug development methods, such as molecular docking, quantitative structure-activity relationship (QSAR) and pharmacophore modeling reduces large-scale blind screening.
 

6. Specific aims

  • a. To discover the novel mechanisms of tumorigenesis, metastasis and drug resistance of cancers with common interests, specifically focus on the endemic cancers with ethnic differences between East and West
  • b To identify druggable pathways and targets
  • c. To develop biomarkers and effective therapies to improve treatment outcome of cancer patients
 

7. Main projects

  1. a. To discover the novel mechanisms of tumorigenesis, metastasis and drug resistance of cancers with common interests, specifically focus on the endemic cancers with ethnic differences between East and West and to identify druggable pathways/targets
  2. b. The role of cancer stem cells (CSC) in metastasis and drug resistance.
  3. c. Development of novel anti-cancer drugs: from mechanisms, animal models to translational medicine