Exploiting the Glycome for Cancer Therapeutics
Exploiting the Glycome for Cancer Therapeutics
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The surfaces of cancer cells frequently express different types and levels of glycoproteins compared to healthy cells, and as a consequence there has been significant interest in them as potential anticancer targets. While there have been some examples of vaccine candidates from early-stage studies, nothing has yet come from these efforts. However, recent advances suggest we are about to see a resurgence in cancer glycomics.
The potential of the glycome in cancer
Professor Mark von Itzstein is a leading chemical glycobiology researcher who headed up the team that discovered the anti-flu drug, Relenza (zanamivir). Now, as Director of the Institute for Glycomics at Griffith University in Australia, he is applying the power of glycomics to the institute’s vision of "fighting diseases of global impact". Cancer is a high priority area.
“We already know that there are significant changes in the glycome (i.e. carbohydrate language on the cell surface) when cells enter a cancerous state,” he explains. “Moreover, as cancers progress, further changes occur that enable cancer cells to mobilize and spread. “Many of these changes provide the cancer cell an advantage such as protection from the immune system or mobilization. Characterizing cancer cell glycomes provides exciting opportunities for novel biomarker discovery that will aid in early diagnostic tools as well as provide new direction in not only drug discovery, but also possible vaccine development.”
To exploit this potential, the Australian Centre for Cancer Glycomics (A2CG) has been established within the institute, making it possible to undertake large-scale studies in cancer glycomics. “We firmly believe that the work undertaken in the centre and institute will transform our understanding of cancer and provide exciting opportunities in novel diagnostics and therapies. Science convergence is becoming the norm and there are so many parallels in the glycomics of infectious diseases and cancer. Cross-fertilization of ideas and concepts will be a natural outcome.”
Current challenges in glycomics
There are some barriers to overcome, however. A major challenge is ensuring access to sufficient well-curated patient specimens for data collection and analysis, says von Itzstein. “We need to have large patient material cohorts to enable statistically significant conclusions. At our institute, we overcome this by ensuring we collaborate with relevant clinician-researchers at hospitals worldwide that have such cohorts.”
A more technical challenge has been the global analysis of glycoproteins from complex biological samples, which is made difficult by the heterogeneity and relatively low abundance of these intriguing molecules. A new high affinity method that exploits the unique properties of glycoproteins may provide a solution.1
“We’ve previously used boronic acid-conjugated beads to enrich glycopeptides from digested yeast whole-cell lysates for global analysis,2” explains senior author of the study, Ronghu Wu, Assistant Professor at the Georgia Institute of Technology, Atlanta, USA. “But the binding affinity of these conventional methods is typically not strong enough to capture low-abundance species.”
To solve this, Wu’s lab followed a two-step approach. First, they attempted to enhance the interactions by evaluating several boronic acid derivatives and found one (benzoboroxole) that allowed the identification of the greatest number of glycopeptides. Next, they exploited a common property of glycoproteins, which is that the vast majority of glycans contain multiple sugars.
“Based on this feature, we synthesized a dendrimer as the platform for synergistic interactions between the favored derivative, benzoboroxole, and the sugars,” explains Wu. “Because the number of benzoboroxole molecules bound to a dendrimer can be easily adjusted and a dendrimer provides the structure flexibility, if a glycan contains several monosaccharides, then multiple boronic acid molecules in a dendrimer can form very strong interactions with the glycan synergistically.”
Using this method, the number of unique glycopeptides identified increased and the interaction was much stronger, which is crucial for enrichment of low-abundance glycoproteins – often those of most relevance in disease. The approach can be used to study glycoprotein dynamics, how glycans affect protein stability and trafficking, and how glycans affect protein interactions with other molecules – such as proteins or metabolites. Wu’s lab is also collaborating with others to compare the glycome from ovarian cancer samples with those from women without the disease.
Cancer glycomics and drug development
In addition to discovery research like this, there is also a resurgence in pursuing glycome targets to develop new treatments against cancer.
One approach being pursued is to use antibodies against glyco-based epitopes that appear on cancer cells, such as the molecule Neu5Gc. Racotumomab is an anti-idiotype monoclonal antibody against NeuGc which had better progression-free and overall survival compared with placebo in a randomized Phase II trial of patients with non-small-cell lung cancer.3 Results are anticipated from a larger, international, randomized Phase III follow-up trial.
A second approach is to target viruses to cancer cells through specific carbohydrate recognition. Recently, a new first-in-class drug based on this approach entered clinical trials. OBI-888 is a monoclonal antibody that targets a glycosphingolipid called Globo H. Sphingolipids are lipid molecules that make up the cell membrane and are found on multiple tumor types. Globo H was first isolated in 1983 and is highly elevated in various types of cancer. OBI-888 has been shown to induce tumor elimination by binding to the cancer cells and recruiting immune cells to kill them. But it also works to halt immunosuppression and to prevent cancers from growing blood vessels, so has all-round potential to treat cancer.
Finally, rather than use the glycan itself as a target, some approaches are exploiting the function of glycans in cancer cell growth. One such approach developed by von Itzstein and colleagues, uses ‘glycoshielding’ to stop the action of the specific carbohydrate-processing enzyme, heparanase.4 They used polynuclear platinum complexes to mask heparan sulphate within the extracellular matrix, which in turn blocked physiologically relevant processes that require heparan sulphate as a substrate. This included the action of the enzyme heparanase, which is required for angiogenesis. In doing so, they switched the profile of platinum drugs from cytotoxic to anti-metastatic by using them against a different (carbohydrate-based) target.
“There is no doubt that we are at the beginning of a major revolution in understanding the relevance of changes in cell-surface glycosylation (the glycome) of various cancers,” says von Itzstein. “The real power of glycomics will be even more realized when the outcomes of other cell-based 'omics' such as genomics, proteomics and lipidomics are integrated through bioinformatics to give a more holistic view of a healthy state versus cancer.”
1. Xiao H, et al. (2018) An enrichment method based on synergistic and reversible covalent interactions for large-scale analysis of glycoproteins. Nat Commun. 9: 1692. doi: 10.1038/s41467-018-04081-3
2. Chen, W et al. (2014) A universal chemical enrichment method for mapping the yeast N-glycoproteome by mass spectrometry (MS). Mol. Cell. Proteom. 13, 1563–1572. doi: 10.1074/mcp.M113.036251
3. Alfonso S. et al. (2014) A randomized, multicenter, placebo-controlled clinical trial of racotumomab-alum vaccine as switch maintenance therapy in advanced non-small cell lung cancer patients. Clin Cancer Res. 20 (14): 3660-3671. doi: 10.1158/1078-0432.CCR-13-1674
4. Peterson EJ. et al. (2017) Antiangiogenic platinum through glycan targeting. Chem Sci. 8 (1): 241-252. doi: 10.1039/c6sc02515c