Drexel University College of Medicine

The Hepatitis B virus (HBV) is the prototypic member of the Hepadnaviridae family of viruses that chronically infects 350 million people worldwide.  The major complication is the development of primary hepatocellular carcinoma (HCC) estimated to cause 500,000 deaths annually.  Although there is no cure for HBV infection, several therapeutic options exist.  However, the poor response rate and development of resistant mutants highlight the need for alternatives and complements to the conventional therapeutic regimens.

Our laboratory has two major projects: the development of new HBV therapeutics and the search for early markers of liver cancer and cirrhosis.  Our approach towards the discovery of HBV therapeutics involves the development of immunological agents to complement traditional anti-virals.  That is, there is a growing body of evidence that animals and people chronically infected with hepadnaviruses possess the potential to mount a beneficial immunological response to the virus.  It appears that this response, in experimental animals and in chronically infected people, can be enhanced or enabled by highly effective and sustained antiviral therapy and vaccination using hepadna viral antigens (Boni et al. Hepatology. 33: 963 2001).  Thus, our approach involves the development of novel HBV DNA vaccines that will be able to generate the appropriate immune response to help cure people of HBV.  This work will lead to great insights into the basic biology of protein folding, degradation, antigen presentation and into the development of useful therapeutic products.  

In an effort to identify serum biomarkers of HCC, we have developed a targeted glycoproteomic approach.  That is, we have utilized a simple quantitative method to identify alterations in glycosylation and subsequently identify the glycoproteins with altered glycosylation, by two-dimensional proteomics (2DE).  In the case of primary HCC, we have shown that an increase in the fucosylation of liver derived glycoproteins is associated with the development of cancer.  By combining our quantitative glycan sequencing methodology with 2DE, we have identified many glycoproteins with altered glycosylation as a function of disease.  One such glycoprotein, GP 73, was found to be elevated and hyperfucosylated in animals with HCC.  Further analysis of human sera from patients with varying disease states confirmed the specific association of GP73 with the development of HCC.  GP73 is a resident Golgi membrane protein that is know to be upregulated in liver disease including viral infection and, although its function has yet to be elucidated, its expression profile suggests it may serve as a biomarker of liver cancer.

Publications

1. :Block, T. M., Comunale, M. A., Lowman, M., Steel, L. F., Romano, P. R., Fimmel, C., Tennant, B. C., London, W. T., Evans, A. A., Blumberg, B. S., Dwek, R. A., Mattu, T. S., and A. S. Mehta.  Use of targeted glycoproteomics to identify serum glycoproteins that correlate with liver cancer in woodchucks and humans.  Proc. Natl. Acad. Sci. U. S. A., 102(3): 779-784, 2005.
2. Simsek, E., Mehta, A., Zhou, T., Dwek, R. A., and T. M. Block.  Hepatitis B Virus Large and Middle Glycoproteins Are Degraded by a Proteasome Pathway in Glucosidase-Inhibited Cells but Not in Cells with Functional Glucosidase Enzyme.  J. Virol., 79 (20): 12914–12920, 2005.
3. Marrero, J. A., Romano, P. R., Nikolaeva, O., Steel, L., Mehta, A., Fimmel, C. J., Comunale, M. A., D'Amelio, A., Lok, A. S., and T. M. Block.  GP73, a resident Golgi glycoprotein, is a novel serum marker for hepatocellular carcinoma.  J. Hepatol., 43(6): 1007-1012, 2005.
4. Drake, R. R., Schwegler, E. E., Malik, G., Diaz, J. I., Block, T., Mehta, A., and O. J. Semmes.  Lectin capture strategies combined with mass spectrometry for the discovery of serum glycoprotein biomarkers.  Mol. Cell Proteomics, 5(10): 1957-1967, 2006.
5. Comunale, M. A., Lowman, M., Long, R. E., Krakover, J., Philip, R., Seeholzer, S., Evans, A. A., Hann, H. W., Block, T. M., and A. S. Mehta.  Proteomic analysis of serum associated fucosylated glycoproteins in the development of primary hepatocellular carcinoma.  J. Proteome Res., 5(2): 308-315, 2006.
6. Dougherty, A. M., Guo, H., Westby, G., Guo, J.-T., Mehta, A., Norton, P., Gu, B., Block, T. M., and A. Cuconati.  A Substituted Tetrazolo-Pyrimidine is a Specific and Novel Inhibitor of Hepatitis B Virus Surface Antigen Secretion.  Antimicrobial Agents and Chemotherapy, 51(12): 4427-4437, 2007.
7. Mehta, A. S., Long, R. E., Comunale, M. A., Wang, M., Rodemich, L., Krakover, J., Philip, R., Marrero, J. A., Dwek, R. A., and T. M. Block.  Increased levels of galactose-deficient anti-Gal immunoglobulin G in the sera of hepatitis C virus-infected individuals with fibrosis and cirrhosis.  J. Virol., 82(3): 1259-1270, 2008.
8. Balagopal, A., Philp, F. H., Astemborski, J., Block, T. M., Mehta, A., Long, R., Kirk, G. D., Mehta, S. H., Cox, A. L., Thomas, D. L., and S. C. Ray.  Human immunodeficiency virus-related microbial translocation and progression of hepatitis C.  Gastroenterology, 135(1): 226-233, 2008.
9. Norton, P. A., Comunale, M. A., Krakover, J., Rodemich, L., Pirog, N., D'Amelio, A., Philip, R., Mehta, A. S., and T. M. Block.  N-linked glycosylation of the liver cancer biomarker GP73. J Cell Biochem., 104(1): 136-149, 2008.
10. Mehta, A., and T. M. Block.  Fucosylated Biomarkers for liver fibrosis, cirrhosis and cancer.  Dis. Markers, 25(4-5): 259-265, 2008.
11. Comunale, M. A., Wang, M., Krakover, J., Rodemich, L., Kopenhaver, B., Long, R. E., Junaidi, O., Di Bisceglie, A. M., Block, T. M., and A. S. Mehta.  Identification and development of fucosylated glycoproteins as biomarkers of primary hepatocellular carcinoma.  Journal of Proteome Research. 8(2): 595-602, 2009.
12. White, K. Y., Rodemich, L., Nyalwidhe, J. O., Comunale, M. A., Clements, M. A., Lance, R. S., Schellhammer, P. F., Mehta, A., Semmes, O. J., and R. R. Drake.  Glycomic Characterization of Prostate Specific Antigen and Prostatic Acid Phosphatase in Prostate Cancer and Benign Disease Seminal Plasma Fluids.  Journal of Proteome Research, 8(2): 620-630, 2009.
13. Simsek, E., Sinnathamby, G., Block, T. M., Liu, Y., Philip, R., Mehta, A. S., and P. A. Norton.  Inhibition of cellular alpha-glucosidases results in increased presentation of hepatitis B virus glycoprotein peptides by MHC class I.  Virology, 384(1): 12-15, 2009.
14. Comunale, M. A., and A. Mehta.  Glycoproteomic analysis by two-dimensional electrophoresis.  Methods Mol. Biol., 520: 59-74, 2009.
15. Wang, M., Long, R. E., Comunale, M. A., Junaidi, O., Marrero, J., Di Bisceglie, A. M., Block, T. M., and A. S. Mehta.  Analysis of GP73 in combination with fucosylated alpha-1-antitrypsin and fucosylated kininogen as a biomarker of hepatocellular carcinoma, Cancer Epidemiology, Biomarkers & Prevention, 18(6): 1914-1921, 2009.