1. Cancer Research Group Joanne Chen Yuh-Shan Jou You-Di Liao Konan Peck Steve R. Roffler Sheau-Yang Shieh Tsann-Long Su Cheng-Wen Wu Pan-Chyr Yang Joint appointment, NHRI Joint appointment, NTUH

2. Cancer Research Group A pipeline integration of technology development, basic, applied, and clinical studies Genomic & proteomic research tool developments Molecular pathogenesis studies Carcinogenesis & metastasis Identification of biomarkers for diagnosis, prognosis and therapy Therapeutic agents and clinical assays development Clinical validation Bench Bedside

3. Genomic and proteomic research tool developments Directed molecular evolution to create new therapeutic proteins (Steve Roffler) Surface expressed proteins for therapy and imaging (Steve Roffler) cytokine antibody enzyme Aptamer arrays for protein- specific expression profiling (Konan Peck) Bioinformatics tools and database for hepatocarcinoma oncogenomics (Yuh-Shan Jou) High throughput transcript-specific expression profiling system (Konan Peck) Model cell lines & multi-well assay for cancer cell invasion studies (Pan-Chyr Yang & Cheng-Wen Wu)

4. Molecular pathogenesis studies (carcinogenesis) -Genetic events associated with pathogenic development of GI-track cancers Rho GTPases & Wnt/  -catenin/TCF pathway Cancer genomics & tumor biology of GI-track cancer (Joanne Chen) Identify and study human hepatocellular carcinoma genes by genomic approaches (Yuh-Shan Jou) - HCC genes somatic mutation screening - Homozygous deletion of chromosome 13q12.11 - Integrated HCC database: OncoDB.HCC for bioinformatics analysis Genome-wide minimal deleted regions, two major tumorigenic pathways, and a homozygous deletion of 13q12.11 in HCC have been identified. 1. Overexpression of RTKN, a Rho GTPase effector, contributes to GC pathogenesis, and its overexpression is associated with GC progression. 2. Abnormal expression of OPN and its receptor CD44 contributes to cancer progression.

5. p53 and cell cycle checkpoints (Sheau-Yann Shieh) - The role of CHK1, CHK2-interacting proteins in checkpoint control - The role of CHK1 and CHK2 in DNA double strand break repair Mol. Biol. Cell 16:1684-1695, 2005 p53 J. Biol. Chem. 280: 7748-7757, 2005 Molecular pathogenesis studies (carcinogenesis) Pathogenesis of human cytomegalovirus (Cheng-Wen Wu) - The functions of the HCMV IE2 protein 1.DNA methylation may be involved in the regulation of the HCMV major IE promoter 2.TE2, a novel protein acetyltransferase that interacts with HCMV IE2, increases the activity of the DNA methyltransferase 1

6. Molecular pathogenesis studies (metastasis) - Genome-wide identification of metastasis related genes (Pan-Chyr Yang & Konan Peck) - Characterize novel and known invasion/metastasis suppressors and enhancers: CRMP-1, HLJ1, LCRMP-1, Slug (Pan-Chyr Yang); TAL6 (Steve Roffler) KLK8 (Konan Peck) - Identification of metastasis-related proteases and protease inhibitors (Cheng-Wen Wu) CRMP-1 PPG to decipher the molecular mechanism of cancer metastasis Clinical studiesCell biology studiesHistology studiesMouse model studies Empirical approaches for validation and characterization

7. Biomarkers identified in the research projects In silico database searchEmpirical genomic approaches Candidate marker genes Biomarkers Validation with cancer cell lines Validation with clinical specimens Validation with mouse models Metastasis and prognosis biomarkers: CRMP-1, LCRMP-1, HLJ1, Slug, KLK 8 TAL6, CD13, CD44, RTKN, OPN Cancer therapy efficacy assessment markers: KRT19, UCHL1, FN1, TRIM28 Drug target for metastasis inhibition: LCRMP-1, Slug

8. Anti-tumor Ribonucleases from Bullfrogs (You-Di Liao) Glucuronide prodrugs for cancer therapy (Steve Roffler) BO-0742 N HN OCH 2 CH 2 N(CH 2 CH 2 Cl) 2 CH 2 OH Gene alkylating agents (in preclinical studies) Topoisomerase II Inhibitors (9-Anilinoacridine Analogues) Topoisomerase I Inhibitors (Camptothecin Analogues) Discovery and Development of Potential Anticancer Agent (Tsann Long Su) Therapeutic agent developments

9. Clinical assay developments Microarray for prognosis of NSCLC patients (Pan-Chyr Yang) Rapid assessment of therapy efficacy and relapse detection method (Konan Peck & Pan-Chyr Yang) Microarray for subtyping of gastric cancers (Joanne Chen) Using marker genes to detect the amount of circulating tumor cells before and after the treatment allows rapid efficacy assessment and relapse detection.

10. Achievements in the past 5 years Publications in academic journalsTechnology transfer to biotech industry Publications in basic research journals American Journal of Respiratory Critical Care Medicine American Journal of Pathology Cancer Research Journal of Biological Chemistry Journal of the National Cancer Institute Molecular Biology of the Cell Oncogene The EMBO Journal. Publications in applied or clinical research journals Bioinformatics Clinical Cancer Research Journal of Clinical Oncology New England Journal of Medicine Nucleic Acids Research.

11. Achievements in the past 5 years Multi-national intellectual property rights Granted patents K. Peck, et al. (2001) US Patent # 6,218,114 K. Peck, et al. (2001) ROC patent 438889 K. Peck, et al. (2002) European Patent EP 0822261 K. Peck, et al. (2003) ROC patent 541340 S.R. Roffler, et al. (2003) US Patent # 6,596,849 S.R. Roffler, et al. (2003) US Patent # 6,617,118 S.R. Roffler, et al. (2003) European Patent EP 0990661 S.R. Roffler, et al. (2004) US Patent # 6,699,972 S.R. Roffler, et al. (2004) ROC Patent 205511 T.L. Su, et al. (2004) US Patent # 6,821,983 K. Peck, et al. (2005) US Patent # 6,867,050 K. Peck, et al. (2005) ROC patent I232867 Pending patent applications P.C. Yang, et al. (2003) European Patent 1271153 A2 P.C. Yang, et al. (2003) US Patent # 20030077624 A1. P.C. Yang, et al. (2003) European Patent 1285970 A2 P.C. Yang, et al. (2003) US Patent # 20030054387 A1. S.R. Roffler, et al. (2004) US Patent # 20040014156 A1. T.L. Su, et al. (2004) US Patent # 20040198765 A1. P.C. Yang, et al. (2005) US Patent # 20050182016 A1. Y.D. Liao, et al. (2005) US Patent # 20050214899 A1. Technology transfers to biotech industry 1. S.R. Roffler, et al. “Monoclonal antibody against polyethylene glycol” to Bayer and Hoffmann-LaRoche 2. K. Peck, et al. “Method for profiling gene expression pattern and isolation of differentially expressed genes” to Taiwan Genome Sciences, Inc. and 4 other companies. 3. K. Peck, et al. “Method for constructing high-density non-redundant gene arrays” to Taiwan Genome Sciences, Inc. and 2 other companies. 4. K. Peck, et al. “Methods for rapid antimicrobial susceptibility testing” to Cold Spring Biotech, Inc. 5. P.C. Yang, et al. “Metastasis-associated genes” to AdvPharma, Inc. 6. P.C. Yang, et al. “Collapsin response mediator protein-1 as tumor metastasis marker” to AdvPharma, Inc.