Metabolic Engineering of Cancer for Selective Immunotargeting Cancer is one of the most common and fatal diseases and, in general, it is difficult to cure. Among the different strategies probed for cancer therapy, treating cancer patients with cancer vaccines or cancer-targeting antibodies is especially attractive as the human immune system can be extremely effective and selective to eliminate tumors in the human body. In the development of cancer vaccines used for patient immunization or antibody preparation, the abnormal glycans expressed by cancer cells, called tumor-associated carbohydrate antigens (TACAs), are valuable molecular targets, as they are abundant, exposed, and conserved on the cancer cell surface. However, the problem is that TACAs are usually poorly immunogenic or tolerated by the patients' immune system, which has severely hindered the delivery of functional TACA-based cancer vaccines or immunotherapies. To address the problem and develop effective cancer cures, a new immunotherapeutic strategy was proposed. First, animals (or patients) are immunized with a vaccine made of an unnatural TACA derivative to elicit a specific immune response. Next, the animals are treated with a similarly modified monosaccharide to bioengineer tumor cell expression of the unnatural TACA derivative (cancer cell glycoengineering). Then, the trained immune system will specifically recognize and kill the glycoengineered tumors. The new immunotherapy can also be realized with a TACA derivative-specific antibody, instead of a vaccine, for the treatment. For the strategy to work, it has to mee two conditions, namely, a potent vaccine that can be used for patient immunization or antibody preparation and an effective method for cancer cell glycoengineering. It has been proved that the latter can exploit the flexible biosynthetic pathways for glycans. To create potent and reliabl TACA-based vaccines, a new vaccine strategy is proposed here, namely, to have TACAs linked to a bacterial monophosphoryl lipid A (MPLA). The hypothesis is that MPLA can act as a powerful vaccine carrier and built-in adjuvant to formulate fully synthetic, self-adjuvanting, structurally defined, readily reproducible, and robust glycoconjugate vaccines. This proposal aims to: (1) study the structure-activity relationship of MPLAs and identify new, potent vaccine carriers and adjuvants, (2) prepare and study the immunological properties of TACA-MPLA conjugates and identify the proper vaccines for cancer immunotherapy, and (3) use the new TACA-MPLA conjugates as vaccines for active and passive immunotherapy of cancer such as melanoma and breast or colon cancer by the above therapeutic strategy. One innovation of this project is the use of MPLA as a carrier and adjuvant for fully synthetic self-adjuvanting carbohydrate vaccine development and related studies. Another innovation is the combination MPLA conjugate vaccine with cell glycoengineering for cancer therapy. This combination will solve the immunotolerance problem of TACAs, a central issue in cancer immunology, and help develop functional cures for various tumors. The new vaccine strategy will be applicable to other vaccine design as well. Thus, both strategies should be widely useful, and this research program should be of general significance and have a broad impact on cancer research.

Public Health Relevance

Cancer immunotherapy or therapeutic cancer vaccine is highly regarded for cancer treatment. To develop efficient cancer immunotherapies, a new strategy that combines vaccination using a synthetic glycoconjugate vaccine and metabolic engineering of specific carbohydrate antigens on the cancer cell surface was explored. This research program aims to discover novel vaccine carriers and adjuvants to formulate potent, structurally defined, and self-adjuvanting cancer vaccines and apply the vaccines to the treatment of melanoma and breast, prostate and colon cancers by the new immunotherapeutic strategy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Salomon, Rachelle
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University of Florida
Schools of Arts and Sciences
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Gao, Jian; Guo, Zhongwu (2018) Progress in the synthesis and biological evaluation of lipid A and its derivatives. Med Res Rev 38:556-601
Li, Qingjiang; Guo, Zhongwu (2018) Pondering the Structural Factors that Affect 1,2-trans-Galactosylation: A Lesson Learnt from 3-O-?-Galactosylation of Galactosamine. J Carbohydr Chem 47:347-362
Li, Qingjiang; Guo, Zhongwu (2017) Synthesis of the Cancer-Associated KH-1 Antigen by Block Assembly of Its Backbone Structure Followed by One-Step Grafting of Three Fucose Residues. Org Lett 19:6558-6561
Zhou, Zhifang; Mandal, Satadru S; Liao, Guochao et al. (2017) Synthesis and Evaluation of GM2-Monophosphoryl Lipid A Conjugate as a Fully Synthetic Self-Adjuvant Cancer Vaccine. Sci Rep 7:11403
Gao, Jian; Guo, Zhongwu (2016) Chemical Synthesis of the Repeating Unit of Type V Group B Streptococcus Capsular Polysaccharide. Org Lett 18:5552-5555
Liao, Guochao; Zhou, Zhifang; Liao, Jun et al. (2016) 6-O-Branched Oligo-?-glucan-Based Antifungal Glycoconjugate Vaccines. ACS Infect Dis 2:123-31
Liao, Guochao; Zhou, Zhifang; Suryawanshi, Sharad et al. (2016) Fully Synthetic Self-Adjuvanting ?-2,9-Oligosialic Acid Based Conjugate Vaccines against Group C Meningitis. ACS Cent Sci 2:210-8
Liao, Guochao; Zhou, Zhifang; Burgula, Srinivas et al. (2015) Synthesis and immunological studies of linear oligosaccharides of ?-glucan as antigens for antifungal vaccine development. Bioconjug Chem 26:466-76
Liao, Guochao; Zhou, Zhifang; Guo, Zhongwu (2015) Synthesis and immunological study of ?-2,9-oligosialic acid conjugates as anti-group C meningitis vaccines. Chem Commun (Camb) 51:9647-50
Mondal, Prolay K; Liao, Guochao; Mondal, Mohabul A et al. (2015) Chemical synthesis of the repeating unit of type Ia group B Streptococcus capsular polysaccharide. Org Lett 17:1102-5

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