Konan Peck Tsann-Long Su Joanne Chen Cheng-Wen Wu Yuh-Shan Jou Steve R. Roffler Joint appointment, NHRI You-Di Liao Sheau-Yang Shieh Pan-Chyr Yang Joint appointment, NTUH Cancer Research Group
Cancer Research Group A pipeline integration of technology development, basic, applied, and clinical studies Genomic & proteomic research tool developments Bench Molecular pathogenesis studies Carcinogenesis & metastasis Identification of biomarkers for diagnosis, prognosis and therapy Therapeutic agents and clinical assays development Clinical validation Bedside
Genomic and proteomic research tool developments High throughput transcript-specific expression profiling system (Konan Peck) Aptamer arrays for protein-specific expression profiling (Konan Peck) Model cell lines & multi-well assay for cancer cell invasion studies (Pan-Chyr Yang & Cheng-Wen Wu) Bioinformatics tools and database for hepatocarcinoma oncogenomics (Yuh-Shan Jou) Surface expressed proteins for therapy and imaging (Steve Roffler) Directed molecular evolution to create new therapeutic proteins (Steve Roffler) enzyme cytokine antibody
Molecular pathogenesis studies (carcinogenesis) Cancer genomics & tumor biology of GI-track cancer(Joanne Chen) • Genetic events associated with pathogenic development of GI-track cancers • Rho GTPases & Wnt/b-catenin/TCF pathway 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. 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.
p53 J. Biol. Chem. 280: 7748-7757, 2005 Mol. Biol. Cell 16:1684-1695, 2005 Molecular pathogenesis studies (carcinogenesis) 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 Pathogenesis of human cytomegalovirus(Cheng-Wen Wu) - The functions of the HCMV IE2 protein • DNA methylation may be involved in the regulation of the HCMV major IE promoter • TE2, a novel protein acetyltransferase that interacts with HCMV IE2, increases the activity of the DNA methyltransferase 1
100 P = 0.019 90 80 Probability of disease free KLK8 high 70 N=22 60 50 KLK8 low 40 N=33 30 0 10 20 30 40 50 60 70 Time in months CRMP-1 Molecular pathogenesis studies (metastasis) PPG to decipher the molecular mechanism of cancer metastasis - Genome-wide identification of metastasis related genes(Pan-Chyr Yang & Konan Peck) - Identification of metastasis-related proteases and protease inhibitors(Cheng-Wen Wu) - Characterize novel and known invasion/metastasis suppressors and enhancers: CRMP-1, HLJ1, LCRMP-1, Slug(Pan-Chyr Yang); TAL6 (Steve Roffler) KLK8 (Konan Peck) Empirical approaches for validation and characterization Cell biology studies Histology studies Mouse model studies Clinical studies
Biomarkers identified in the research projects In silico database search Empirical genomic approaches Candidate marker genes Validation with cancer cell lines Validation with mouse models Validation with clinical specimens Biomarkers 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
O C H C H N ( C H C H C l ) 2 2 2 2 2 H N C H O H 2 BO-0742 N N H 2 M e , O M e H N N R R 2 1 5 - ( 9 - a c r i d i n y l a m i n o ) t o l u i d i n e s 5 - ( 9 - A c r i d i n y l a m i n o ) a n i s i d i n e s Therapeutic agent developments Discovery and Development of Potential Anticancer Agent (Tsann Long Su) Gene alkylating agents (in preclinical studies) Topoisomerase II Inhibitors (9-Anilinoacridine Analogues) • Topoisomerase I Inhibitors (Camptothecin Analogues) Glucuronide prodrugs for cancer therapy (Steve Roffler) Anti-tumor Ribonucleases from Bullfrogs (You-Di Liao)
Clinical assay developments Microarray for prognosis of NSCLC patients (Pan-Chyr Yang) Microarray for subtyping of gastric cancers (Joanne Chen) Rapid assessment of therapy efficacy and relapse detection method (Konan Peck & Pan-Chyr Yang) Using marker genes to detect the amount of circulating tumor cells before and after the treatment allows rapid efficacy assessment and relapse detection.
Achievements in the past 5 years Publications in academic journals Technology 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 . . .
Achievements in the past 5 years Multi-national intellectual property rights 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. 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 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.