Glioblastoma multiforme (GBM) is the most aggressive type of primary brain tumor in humans and accounts for 52% of all primary brain tumor cases. Patients afflicted with GBM usually die within two years of diagnosis. Under the guidance of Assistant Professor of Chemistry Nicole Snyder, Taylor Adams ’11 and Kevin Graepel ’11 spent the summer working on the development of a carbohydrate-based vaccine for GBM. They performed their research in collaboration with Dr. Peter H. Seeberger’s group at the Max Planck Institute for Colloids and Interfaces, Department of Biomolecular Systems in Berlin, Germany.
Today the most common methods for the treatment of GBM are palliative and include surgery, radiation therapy, and chemotherapy. More recently, a number of tumor-pulsed dendritic cell vaccines have also been developed. These vaccines involve collecting proteins specifically associated with cancer cells from individual patients and exposing them to dendritic cells (specialized immune cells that present foreign substances called antigens to immune cells which breakdown the antigens) harvested from the patients. These dendritic cells are taught to recognize the cancer associated proteins using a serious of biomolecular techniques, and infused back into the patient where they begin to target and destroy cells expressing cancer associated proteins.
While these vaccines have improved the prognosis for many patients with GBM, they remain patient specific and are constrained by the amount of time required to obtain peptide antigen from individual tumor cell lines. In addition, resistance is more likely to develop against peptide-based therapeutics since peptide biosynthesis is under direct genetic control. Therefore, a more effective and tumor specific therapeutic that is resistant to genetic transformation is needed to treat GBM.
Recently researchers have determined that certain glycans are associated with diseased states such as GBM. Glycans are branched polymers of carbohydrates that cover the outermost surface of cells and play key roles in cellular communication and cell-to-cell interaction. The addition of glycans to cellular proteins occurs after translation (the production of the peptide), limiting the chances that a genetic mutation could result in resistance. Therefore, generating vaccines against these antigens may present an alternative to peptide-based therapeutics for the treatment of GBM.
Snyder, Adams, and Graepel have been developing a vaccine based on the expression of A2G2F, an N-linked glycan found in high concentrations on the surface of GBM tumors. Thus far, Snyder, Adams and Graepel have nearly completed work on six monosaccharide (single sugar) building blocks which are necessary to synthesize A2G2F. The next phase of this project will focus on the use of an automated oligosaccharide synthesizer to produce the final glycan structure.
Automated solid phase oligosaccharide synthesis was pioneered by Dr. Seeberger and coworkers while at the Massachusetts Institute of Technology. Automated solid-phase oligosaccharide synthesis uses an automated synthesizer to make glycosidic (carbohydrate-carbohydrate) linkages in a similar manner to the way peptide synthesizers are used to make peptide linkages. In general, selectively functionalized monosaccharide building blocks are added sequentially to a growing oligosaccharide chain linked to a solid support by selectively activating the appropriately functionalized monosaccharide building block in the presence of the acceptor. The oligosaccharide is then removed from the solid support and further functionalized for use. Dr. Seeberger’s continued work in this area has led to the development of oligosaccharide synthesizers that can reliably prepare complex glycans such as A2G2F in a few days—a process which used to take months to years. Dr. Seeberger and coworkers were recently highlighted in the latest edition of Nature (Nature 2010, 466,1029) for their work in this area.
Following synthesis and purification, the A2G2F glycan will formulated and evaluated as a potential vaccine candidate. Snyder will remain at the Max Planck Institute through August 2011 as part of her pre-tenure sabbatical to complete this work.
Adams is a senior chemistry major and 2010 Goldwater Recipient. He is planning to attend graduate school upon graduation from Hamilton College this year. Graepel, also a senior chemistry major and 2010 Goldwater Honorable Mention, is planning to pursue an M.D./Ph.D. degree after taking a year or two to conduct research upon graduation.
Today the most common methods for the treatment of GBM are palliative and include surgery, radiation therapy, and chemotherapy. More recently, a number of tumor-pulsed dendritic cell vaccines have also been developed. These vaccines involve collecting proteins specifically associated with cancer cells from individual patients and exposing them to dendritic cells (specialized immune cells that present foreign substances called antigens to immune cells which breakdown the antigens) harvested from the patients. These dendritic cells are taught to recognize the cancer associated proteins using a serious of biomolecular techniques, and infused back into the patient where they begin to target and destroy cells expressing cancer associated proteins.
While these vaccines have improved the prognosis for many patients with GBM, they remain patient specific and are constrained by the amount of time required to obtain peptide antigen from individual tumor cell lines. In addition, resistance is more likely to develop against peptide-based therapeutics since peptide biosynthesis is under direct genetic control. Therefore, a more effective and tumor specific therapeutic that is resistant to genetic transformation is needed to treat GBM.
Recently researchers have determined that certain glycans are associated with diseased states such as GBM. Glycans are branched polymers of carbohydrates that cover the outermost surface of cells and play key roles in cellular communication and cell-to-cell interaction. The addition of glycans to cellular proteins occurs after translation (the production of the peptide), limiting the chances that a genetic mutation could result in resistance. Therefore, generating vaccines against these antigens may present an alternative to peptide-based therapeutics for the treatment of GBM.
Snyder, Adams, and Graepel have been developing a vaccine based on the expression of A2G2F, an N-linked glycan found in high concentrations on the surface of GBM tumors. Thus far, Snyder, Adams and Graepel have nearly completed work on six monosaccharide (single sugar) building blocks which are necessary to synthesize A2G2F. The next phase of this project will focus on the use of an automated oligosaccharide synthesizer to produce the final glycan structure.
Automated solid phase oligosaccharide synthesis was pioneered by Dr. Seeberger and coworkers while at the Massachusetts Institute of Technology. Automated solid-phase oligosaccharide synthesis uses an automated synthesizer to make glycosidic (carbohydrate-carbohydrate) linkages in a similar manner to the way peptide synthesizers are used to make peptide linkages. In general, selectively functionalized monosaccharide building blocks are added sequentially to a growing oligosaccharide chain linked to a solid support by selectively activating the appropriately functionalized monosaccharide building block in the presence of the acceptor. The oligosaccharide is then removed from the solid support and further functionalized for use. Dr. Seeberger’s continued work in this area has led to the development of oligosaccharide synthesizers that can reliably prepare complex glycans such as A2G2F in a few days—a process which used to take months to years. Dr. Seeberger and coworkers were recently highlighted in the latest edition of Nature (Nature 2010, 466,1029) for their work in this area.
Following synthesis and purification, the A2G2F glycan will formulated and evaluated as a potential vaccine candidate. Snyder will remain at the Max Planck Institute through August 2011 as part of her pre-tenure sabbatical to complete this work.
Adams is a senior chemistry major and 2010 Goldwater Recipient. He is planning to attend graduate school upon graduation from Hamilton College this year. Graepel, also a senior chemistry major and 2010 Goldwater Honorable Mention, is planning to pursue an M.D./Ph.D. degree after taking a year or two to conduct research upon graduation.
