Forging ahead in their quest to develop effective carbohydrate-based vaccines, a research team led by Academia Sinica President, Dr. Chi-Huey Wong, and Associate Research Fellow, Dr. Chung-Yi Wu of the Genomics Research Center (GRC) recently developed vaccine candidates against prostate cancer and the pathogen that causes meningococcal meningitis, and have made further progress in understanding the connection between molecule of interest SSEA4 and the spread of cancer cells. The related research was recently published in three articles in top chemistry journals.

Cell surfaces are coated by sugar structures (glycans), which often differ on normal human cells and on bacteria or diseased cells (such as cancer cells). The differences in these sugar structures help disease cells to evade attacks from host immune systems and make diseases more deadly. They can also be exploited to develop anti-bacterial/anti-cancer vaccines, or used as early cancer detection tools; therefore, identifying and understanding these molecules has become an important topic in glycoscience research.

In research published in July in the prestigious Journal of the American Chemical Society, the team from the GRC detailed the synthesis of a vaccine candidate that induced effective, specific antibodies to eradicate prostate cancer cells in mice. Prostate cancer is the most common cancer for men in developed countries such as the USA. As the fatality rate increases gradually every year, prevention and treatment for the prostate cancer are urgently needed. In 2005, Dr. Hakomori discovered that the amount of RM2 antigen increases as prostate cancer progresses; therefore, RM2 antigen is an excellent biomarker for prostate cancer staging and a good target for developing prostate cancer vaccine. The research team from the GRC is the first ever to successfully synthesize this complex glycan molecule and further attach it to carrier protein CRM197 to create a prostate cancer vaccine candidate, which was combined the previously developed glycolipid adjuvant C34 for vaccine tests in a mice animal model.

　　The research team also synthesized the capsular sugars of the important but problematic Neisseria meningitidis (meningococcus bacteria) SerogroupW135 and then used them to synthesize vaccines and test them on mouse models using the same strategy as with the prostate vaccine research above. The results showed that the vaccines successfully induced antibodies to neutralize the sugar structures. The vaccines then were further examined to demonstrate the bactericidal activity of various lengths of sugars, and the results showed that the length as short as tetrasaccharide (with 4 sugars) could sufficiently induce bactericidal activity. The effectiveness of this synthesized vaccine may revolutionize the requirement of high biosafety level for current Neisseria meningitides vaccine production, in which the necessary polysaccharides are acquired from pathogenic bacteria and often exist as mixtures of many components. This study also provides a new approach to obtain the necessary polysaccharides by synthesis to create a molecular vaccine that is homogeneous, more consistent, and better quality controlled. This research has been published in the prestigious German journal, Angewandte Chemie International Edition.

　　Besides these exciting results in vaccine developments, this research team also furthered understanding of the correlation between breast cancer marker, SSEA-4, and spread of cancer. SEEA-4 (a hexasaccharide glycolipid with sialylated end), is considered to be a human stem cell marker. The research team previously discovered that SSEA-4 is highly expressed on breast cancer cells and breast cancer stem cells but not found on normal cells. Moreover, some studies have reported SSEA-4 is related to cancer progression; therefore, SSEA-4 is considered an excellent target for designing breast cancer vaccine or treatment antibody, but the functions and mechanism of SSEA-4 are still not fully understood. The research team used SSEA-4 magnetic beads and glycan microarray to identify FKBP4 as specific binding protein for SSEA-4 in breast cancer cells (MCF-7). The team further found that FK-506, the known FKBP4 inhibitor, can reduce the activity of FKBP4 in the MCF-7 and, thus, decrease the distribution of SSEA-4 on MCF-7. This study also confirmed that FKBP4 is the carrier to transport SSEA-4 to surface after it was synthesized in the cell. Prior to this study, scientists have found that using FK-506 to inhibit the expression of FKBP4 can reduce tumor cell metastasis. Thus, the team speculated that reducing expression of SSEA-4 on cancer cells or inducing SSEA-4 antibody (e.g. the new generation breast cancer vaccine developed by this research group) can effectively reduce the probability of tumor cell metastasis. This study not only sheds light on the ap 15500 relationship between SSEA-4 and cancers but also provides important information for cancer treatment. The results have also been published in prestigious Journal of the American Chemical Society.

　　The technologies related to the prostate cancer and Neisseria meningitides SerogroupW135 vaccines have been transferred to a biotech company for further development.

　　The first author of the prostate cancer vaccine development article is Dr. Hong-Yang Chuang of the Chemistry Department, National Taiwan University. The first author of Neisseria meningitides Serogroup W135 vaccine development article is Dr. Chia-Hung Wang of the joint Ph.D. program of the Genomic Research Center, Academia Sinica and Institute of Biochemistry and Molecular Biology, National Yang-Ming University. And the first author of the study of the relationship between breast cancer marker SSEA-4 and cancer spread is Dr. Ting-Chun Hung, of the Chemistry Department, National Taiwan University.

List of publications:

1. Chuang, H.-Y., Ren, C.-T., Chao, C.-A., Wu, C.-Y., Shivatare, S. S, Cheng, T.-J. R., Wu, C.-Y., Wong, C.-H. “Synthesis and Vaccine Evaluation of the Tumor Associated Carbohydrate Antigen RM2 from Prostate Cancer.” J. Am. Chem. Soc. 2013, 135, 11140-11150.
http://pubs.acs.org/doi/pdf/10.1021/ja403609x

2. Wang, C.-H., Li, S.-T., Lin, T.-L., Cheng, Y.-Y., Wang, J.-T. Wang, Cheng, T.-J.R., Wong, C.-H., Wu, C.-Y.“Synthesis of Neisseria meningitidisserogroup W135 capsular oligosaccharide for immunogenicity comparison and vaccine development.”Angew.Chem. Int. Ed. 2013, 52, online.
http://onlinelibrary.wiley.com/doi/10.1002/anie.201302540/pdf

3. Hung, T.-C., Lin, C.-W., Hsu, T.-L., Wu, C.-Y., Wong, C.-H. “Investigation of SSEA-4 Binding Protein in Breast Cancer Cells”, J. Am. Chem. Soc., 2013, 135, 5934-5937.
http://pubs.acs.org/doi/pdf/10.1021/ja312210c