| Project Title: | Investigating the Biomarkers for Diagnosis and Prognosis of Hepatocellular Carcinoma | |
| Cancer Site: | Liver | |
| Principal Investigator(s): |
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| Participating Institutions: |
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| Clinical Samples: | Tissue banks | |
| Animal Model(s): |
For in vivo validation of HCC biomarkers (Yang, Z.F. et al., Cancer Research 65(1):219, 2005)
For in vivo lead target evaluation (Liu, Y. et al., Cancer Research 65(9):3691, 2005) |
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| Technical Approaches: |
2-DE PAGE/ DIGE tissue profiling and tandem MS/MS
Deep Proteome™ serum profiling and SELDI-ToF MS Cellular membrane proteins and glycopeptide enrichment Tissue microarray Hybridoma and phage-display antibody library |
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Objectives & Deliverables:
Hepatitis B virus (HBV) infection is one of the most common viral infections in humans. The sequelae of chronic HBV infection, such as hepatitis, cirrhosis and hepatocellular carcinoma (HCC), are determined by the dynamic interaction between the virus and the mainly genetically-determined host response. Approximately 2 billion people have been infected with HBV and 350 million of them became chronically infected, mostly in the Asia Pacific region. Among them, around 25-40% will eventually die of liver diseases (viz. cirrhosis with or without hepatocellular carcinoma). Patients with HCC are often presented at late stage of the disease at the time of diagnosis. Examination of the alpha-fetoprotein (AFP) level has been proven to be an effective way to diagnose HCC and its recurrence. However, about 30-40% of HCC patients in China are AFP negative. Besides, there are a large number of patients with hepatitis and cirrhosis who are AFP false positive, rendering this marker less accurate and ineffective for HCC. As such, there is an urgent need to pursue a unique malignancy biomarker in diagnosing AFP-negative HCC and excluding those AFP false positive cirrhotic patients.
The objective of this study is to identify biomarkers for diagnosis and prognosis of HCC as well as for monitoring disease progression by employing proteomic approach. Today, we have analyzed over 100 pairs of HCC tissues and adjacent non-tumor tissues by 2-DE, with 20 healthy liver samples (residual graft) as normal control subjects. Furthermore, serum profiling of the corresponding serum samples were assayed by SELDI-ToF-MS system. Clinical correlation of the proteome profiles or selected biomarkers with defined pathological features (e.g. tumor staging, hepatitis, microvessel density, venous infiltration, recurrence and overall survival) are under intense investigation.
Protein spots identified on a 2-D gel matrix of cancer proteome will be picked up as potential HCC biomarkers or targets for biochemical identification and characterization using MS/MS (Q-STAR and ABI4700). Phage or hybridoma monoclonal antibody (mAb) against these proteins will be generated for screening the specificity as HCC biomarkers by Western blot and immunohistochemistry. Our team has successful record in designing mAb or its derivatives for diagnostic assays and other clinical applications (with a number of US patents filed). We will examine the usefulness of these specific mAbs conjugated with chemotherapeutic agents and potential lead compounds to eradicate HCC tumors in animal models, prior to further prospective clinical trials.
Chi Ming CHE, Ph.D. (Chair Professor of Chemistry, HKU—Key Investigator) [cmche@hkucc.hku.hk]
Dr. Che is a distinguished chemist with diverse interests ranging from inorganic/organic synthesis, chemical luminescence, and chemical biology. He has more than 400 publications in leading Chemistry journals and ranked as the 249th most cited chemist worldwide. After graduation at HKU, he studied at California Institute of Technology. Professor Che has received several prizes and awards, including Croucher Senior Research Fellowship, Distinguished Researcher Award, National Outstanding Young Scholar Award from The National Science Foundation of China, and he is an Academician of Chinese Academy of Sciences.
Sheung Tat FAN, M.S., M.D., Ph.D. (Chair Professor of Surgery, HKU—Biomarker Team Co-PI) [hrmsfst@hkucc.hku.hk]
Dr. Fan is an internationally renowned expert in hepatobiliary surgery and liver transplantation. He has published over 480 papers, received many prizes/awards including the Croucher Senior Medical Fellowship and Distinguished Research Achievement Award—the highest research award conferred by HKU.
Dr. X.Y. GUAN (Clinical Oncology, HKU)
Dr. Q.Y. HE (Institute of Molecular Biology, HKU)
Professor P.B.S. LAI (Surgery, CUHK)
George K.K. LAU, M.D. (Associate Professor of Medicine, HKU—Key Investigator) [gklau@netvigator.com]
Dr. Lau pioneered the work of HBV viral kinetics for the design of combination therapy and adoptive immune transfer in serological clearance of HBsAg. He was also awarded the 973 National Basic Science Research Grant for the study of immunotherapy for chronic HBV infection. Recently, he has also been appointed Jury for the European Consensus for hepatitis B infection and served as member of the Asia-Pacific Consensus panel for hepatitis.
Dr. P.Y. LEE (Surgery/Medicine, HKU)
John M. LUK, Dr.Med.Sc. (Associate Professor of Surgery, HKU—Biomarker Team Co-PI) [jmluk@hkucc.hku.hk]
Dr. Luk received doctoral training at Karolinska Institute and established expertise in HCC, cell adhesion molecules, and antibody engineering. He has published 70 international papers and 2 U.S. patents, and deposited 33 novel DNA sequences in the PubMed GeneBank database. He recently received a Visiting Professorship of Medicine at Harvard Medical School.
Dr. W.W. MAK (Genome Center, HKU)
Irene O.L. NG, M.D. (Professor of Pathology, HKU—Key Investigator) [iolng@hkucc.hku.hk]
Dr. Ng is an experienced hepatopathologist with a strong publication record (over 200 papers) in this field, covering molecular genetics, pathobiology, and prognostic factors of this cancer. She is also a recipient of Croucher Senior Medical Fellowship and a member of the International Liver Cancer Study Group and visiting professor of Shanghai Cancer Institute.
Dr. R.T.P. POON (Surgery, HKU)
Dr. T.C.W. POON (Medicine, CUHK)
Dr. A. SIU (Chemistry, HKU)
Professor P.K.H. TAM (Surgery/Genome Center, HKU)
Lap-Chee TSUI, Ph.D. (Vice-Chancellor, HKU—Key Investigator) [tsuilc@hkucc.hku.hk]
Dr. Tsui pioneered the field in human genetics. In 1989, he identified the defective CFTR gene that causes cystic fibrosis, and has received numerous awards for his research, such as the Gairdner Award. Professor Tsui is a Foreign Associate of the National Academy of Sciences (USA), Fellow of the Royal Society of London, Fellow of Academia Sinica, and Honorary Fellow of Royal College of Physicians (UK). Professor Tsui is the PI of the Hong Kong Team of the International HapMap project.
Genome Research Center (HKU) led by Prof. L.C. Tsui and Prof. P.K. Tam is involved in the International HapMap Project. The Genome Center also provides services in genotyping, microarray and proteomics. Other services including DNA sequencing, FISH, CGH, quantitative PCR, oocyte/blastocyte injection, cryopreservation, flow cytometry, confocal microscopy, tissue arrayer, laser microdissection, histopathology / immunostaining service, polyclonal and monoclonal antibody production, human lymphoblastoid cell lines, and transgenic/knockout service.
genome.hku.hk
Bioinformatic Facilities (HKU) led by Professor F.Y. Chin (Ph.D., Princeton) and Dr. T.W. Lam (Ph.D., UWash), provide technical supports on Design and Analysis of Algorithms, Database Security, Scheduling, Parallel and Distributed Computing, Algorithms in Computational Biology, and Data Mining. The center is also developing computer databases and algorithms for the purpose of speeding up and enhancing biological research, under the auspice of BIOSUPPORT project which is formed with collaboration between HKUCC (The University of Hong Kong Computer Centre), HKU-Pasteur Research Centre and Centre de Ressources INFOBIOGEN (France), with the funding support from the Innovation and Technology Commission, HKSAR government.
bioinfo.hku.hk
Institute of Molecular Technology for Drug Discovery and Synthesis (HKU) led by Professor C.M. Che aims to implement world-class research and development in the area of drug discovery and synthesis, as well as to lay the technical foundation for high-technology pharmaceutical and agrochemical industries in Hong Kong and neighbouring regions. The institute is also equipped with NMR Spectrometers (Bruker AV600 NMR Spectrometer, JEOL 270 NMR Spectrometer), X-Ray Diffractometers (Rigaku AFC7R, MAR research Image plate scanner, Bruker AXS SMART CCD diffractometer) and Mass Spectrometers (ABI Q-STAR, Finnigan MAT-95 with EI, CI, FAB and GCMS, Finnigan LCMS system).
imt.chem.hku.hk
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