(100CA026)Identifying Novel Biomarkers, Therapeutic Targets and Treatments for Invasion, Early Recurrence and Metastasis of Human Hepatoma (I)

The therapeutic efficacy for hepatocellular carcinoma (HCC) remains poor, mainly due to unusually high intrahepatic invasion and recurrence and no effective therapies for recurrence and advanced HCC. To identify the markers for selection of the subgroup of patients with high recurrence risk for adjuvant therapy and to identify new therapeutic targets for treatment and/or prevention from recurrence are our long-term objectives. Recently we identified stathmin1 and ERBB3-depedent signaling are candidate biomarkers and therapeutic targets. We will further investigate their clinical applications and extend our findings to contribute to personalized anti-HCC therapy. The specific aims are: 1) To genomewide isolate genes regulated motility and invasion of HCC directly from HCC tissues. A high efficiency method for genomewide search will be used. Besides Stathmin1 (STMN1) and ERBB3 identified recently, we intend to find more markers and targets because multi-markers (signatures) and multi-targets are usually better than mono-marker and mono-targets in diagnosis and treatment of cancer diseases, respectively. 2) To confirm ERBB3, STMN1 and additional candiate markers for invasion and metastasis. We compare the diagnostic accuracy between multi-markers and single markers in prediction of tumor invasion and recurrence using tissue sections from 100 cases with HCC. 3) To identify serum markers for HCC invasion and prediction of early recurrence. Tumor-specific proteins and/or their metabolites are usually shed into circulation. The newly identified candidates including secreted ERBB3 and IGFBP2 will be examined as serum markers for HCC invasion and metastasis. 4) To elucidate the mechanisms leading to overexpression and/or aberrant activation of ERBB3, IGFBP2, and newly identified invasion genes Gene copy numbers, mutations, and abnormal transcription activation mechanisms of these candidate invasive genes will be examined, so as to identify HCC-specific mutations as biomarkers for diagnosis and treatment. 5) To identify the pathways in which stathmin1, ERBB3, and the newly identified genes involved to regulate HCC invasion and recurrence 6) To validate and optimize the tissue and serum markers for diagnosis, detection of invasion, and prediction of early recurrence of HCC All of the candidate markers including stathmin1 and ERBB3 will be further validated with clinical samples from other than our hospital (Taiwan Liver Cancer Network). The accuracy between single and multi-markers (signatures) in diagnosis, detection of invasion and prediction of recurrence of HCC will be verified. These steps are critical for future commercialization for clinical uses. 7) To establish cell and orthotopic xenograft models to evaluate the roles of newly identified genes as candidate targets in treatment of HCC invasion and metastasis. Inducible expression of cDNA or shRNA targeting candidate genes will be used to establish cell models and orthotopically xenograft animal models. They will be used for mechanistic and pathway studies and for new drug screening and for testing therapeutic efficacy and toxicity in animals, respectively. Through this study, two serum markers have been filed for patent application. We expect that the candidate biomarkers and therapeutic targets for HCC invasion and early recurrence can be commercialized for clinical applications in the near future.

Project ID:PC10006-0136
External Project ID:NSC100-2325-B182-001