Faculty

Heat shock protein 90 (Hsp90) superchaperone complex, which consists several cochaperones (such as Hsp90, Cdc37, Hop, Hsp70, Hsp40, and p23), is involved in various cancers by regulating the maturation and folding of many oncogenic proteins. One of our research projects is to study protein-protein interactions in Hsp90 superchaperone complex and to identify small molecules that disrupting these protein-protein interactions for cancer therapeutics. We utilize mutagenesis and purified protein to investigate the mechanism of Hsp90-Cdc37 interaction in cancers. High throughput screening and molecular modeling is used to identify possible drug candidate to block protein-protein interactions in the Hsp90 superchaperone complex. The candidate is optimized and evaluated for its mechanism to block protein-protein interactions in vitro and in cancer cells. The drug efficacy by blocking protein-protein interactions is investigated in preclinical animal cancer models.

In addition, our laboratory also identifies natural products and synthetic compounds that target cancer stem cells (CSC) for chemoprevention and therapeutics. These products are evaluated to inhibit breast cancer stem cells through Hsp90, AKT, and Wnt/beta-catenin signaling. Since cancer stem cells have been suggested to be responsible for tumor initiation, recurrence, and resistance, the identification of these CSC targeting compounds may provide effective prevention and treatment for breast cancer.

During these drug discovery and development programs from our lab and other labs, we also study the drug metabolism in vitro and pharmacokinetics (ADME and modeling) in vivo preclinical animal model and clinical setting to optimize drug candidates and dose regimen for further development.

Another focus of our research is targeted drug delivery of cancer therapeutic compounds.  We are developing multifunctional nanoparticle (“theranostics”), which contains a tumor targeting moiety (antibody and peptide), a cancer therapeutic compound (Hsp90 inhibitor), a MRI contrast agent (magnetic iron oxide nanoparticle), and a fluorescence probe, for both targeted drug delivery and multimodality tumor imaging.

Representative Publications

1. Li, Y., Zhang, T., Jiang, Y., Lee, S.F., Schwartz, S.J., and Sun, D., "Epigallocatechin-3-gallate Inhibits Hsp90 Function by Impairing Hsp90 Association with Co-chaperones in Pancreatic Cancer Cell Line Mia Paca-2", Mol. Pharmaceutics, 2009, in press.

2. Zhang, T., Hamza, A., Cao, X., Wang, B., Yu, S., Zhan, C.G., and Sun, D., "A Novel Hsp90 inhibitor disrupts Hsp90-Cdc37 complex for pancreatic cancer therapy. Molecular Cancer Therapeutics", Mol. Can. Ther., 2008, 7, 162.

3. Cao, X., Bloomston, M., Jia, G., Frankel, W.L., Zhang, T., Hall, N., Cheng, H., Knopp, M., and Sun, D., Simultaneously Targeting Hypoxic Cancer Cells by HSP90 Inhibitor and Glycolysis Inhibitor in Pancreatic Cancer Therapy", Clin. Can. Res., 2008, 14, 1831.

4. Cao, X., Wang, B., Jia, G., Yang, M., Knopp, M.V., and Sun, D., "Non-invasive tumor MRI imaging and synergistic anti-tumor effect of HSP90 inhibitor and glycolysis inhibitor in RIP1-Tag2 transgenic pancreatic tumor model", Can. Chemo. Pharma., 2008, 62, 985.

5. Fang, L., Holford, N.H.G., Hinkle, G., Cao, X., Bloomston, M. P., Xiao, J.J., Gibbs, S., Al Saif, O.H., Dalton, J.T. Chan, K.K., Scholm, J., Martin, E., and Sun, D., "Population Pharmacokinetics of Humanized Monoclonal Antibody HuCC49∆CH2 and Murine Antibody CC49 in Colorectal Cancer Patients", J. Clin. Pharma., 2007, 47, 227.

6. Fang, L., Zhang, G., Li, C., Zheng, X., Zhu, L., Xiao, J.J., Szakacs, G., Nadas, J., Chan, K.K., Wang, P.G., and Sun, D., "Discovery of a Daunorubicin Analogue That Exhibits Potent Antitumor Activity and Overcomes P-gp-Mediated Drug Resistance", J. Med. Chem., 2006, 49, 932.

7. Fang, L., Battisti, R.F., Cheng, H., Reigan, P., Xin, Y., Shen, J., Ross, D., Chan, K.K., Martin Jr., E.W., Wang, P.G., and Sun, D., "Enzyme Specific Activation of Benzoquinone Ansamycin Prodrugs Using Humanized HuCC49CH2-alpha-Galactosidase Conjugates", J. Med. Chem., 2006, 6290.