Research in Our Laboratory
Our main research focuses on the following three areas:
1. Understanding the pathogenesis, biomarker and therapeutic development for liver cancer:
Our lab has developed a research program to understand pathogenesis, to discover biomarkers, and to develop novel therapies for liver cancer (HCC). Liver cancer is one of the most common and most fatal cancers in the world. Currently there is no effective treatment for this cancer. Our studies on HCC focus on two aspects: 1) the role of epigenetic regulation in HCC, and 2) the mechanisms of epithelial mesenchymal transition (EMT) in HCC cancer aggressiveness and metastasis. We have generated and published a comprehensive whole genome DNA methylation landscape in HCC associated with HBV, HCV infection and alcohol exposure. Our lab is the first to report culture of circulating HCC cells from the blood and discover the connection between HGF/cMET and EMT in HCC metastasis. For biomarker discovery, we have focused on identification of cancer-specific biomarkers using aptamer technology. A few candidates have been characterized. We have established aptamer-chemotherapeutic agent conjugates for liver cancer therapy. Two candidate conjugates are in the process of early clinical trial. For developing therapeutic strategies, we have studied and characterized TRAIL agonists and surviving inhibitors for liver cancer therapy. Agonists that specifically induce liver cancer apoptosis have been studied using cellular and animal models developed in our laboratory. Furthermore, we also developed an immunotherapy program in HCC by focusing on cancer vaccine and CAR-T cell approach. HCC-specific CAR-T cells have been generated and are in the process of testing their anti-HCC therapy.
2. Determining the innate and adaptive immune responses to Hepatitis C viral infection:
This research program was to investigate the innate and adaptive immunity in HCV infection. We have focused on the role of innate antiviral molecular network in human liver cells. Through genetic and biochemical analysis, we have found that liver cells have unique properties to control viral infections. Further molecular characterization of liver-cell innate immunity has revealed the role of Jak-Stat and MAP kinase pathways in the activation of intracellular antiviral state. These investigations have provided significant insights into the mechanisms of interferon antiviral activity and resistance and the virus-host interactions. We have also established cellular and animal models for HCV infection and liver cancers. Using these models, we have identified the key molecular mechanisms that control cytotoxic T-cell immune function against viral replication. We believe the ongoing work will eventually assist us in the development of immunotherapy and effective vaccines. We have also identified several small molecules that prevent viral entry into human hepatocytes. These small molecules are potentially a new class of anti-HCV drugs.
3. Developing PDX mouse models and cancer cell lines for precision cancer medicine:
The new concept of “personalized clinical trial” has been proposed and is currently gaining steam, but the efficiency and broad application of this concept remains to be determined. There is an urgent need to develop more faithful and robust preclinical models to advance precision cancer treatment. PDX models have been used as tools to more closely mimic human malignancies in many laboratories, including our own. The model represents an emerging platform for translational cancer research. We have established approximately 60 PDX models, including pancreatic cancer, liver cancer, lung cancer, colon cancer, sarcoma, and melanoma. We are now working on PDX models with humanized immune system and 3-dimensional organoid culture models of different cell types.