The Sweet and Sour of Cancer: Glycans as Novel Therapeutic Targets

Mark M. Fuster; Jeffrey D. Esko

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Implications and Future Directions

A few important patterns emerge from the above discussion. First, a given glycan might act at different stages of tumour progression, so targeting that glycan might have broad effects (Fig. 3). Second, at any given stage of progression, a specific glycan-targeting strategy might alter several glycan-dependent interactions. For example, altering selectin interactions would affect platelet, lymphocyte and endothelial adhesion. Third, some therapeutic strategies can target more than one class of glycan-protein interaction. For example, heparin will block selectin-SLeX interactions and also block invasion and angiogenesis by inhibiting heparanases and growth-factor interactions with their receptors. Alternatively, metabolic decoys might alter tumour-cell interactions that are mediated by selectins and affect the immunogenicity of carcinoma mucins ( Box 1 ). Altering N-glycosylation of tumour glycoproteins might confer additional biological effects by affecting the folding of several crucial membrane proteins.[145] Finally, one should also consider the potential synergistic effects of altering tumour glycans in combination with existing radiotherapeutic and chemotherapeutic therapies or anti-angiogenic therapies. An added advantage of this approach is that it might also overcome the problems of tumour heterogeneity and drug resistance, which are concerns that are inherent in any specific targeting of tumour cells.

Ultimately, the choice and timing of any future glycan-based therapy against cancer should be guided by both serological assays for glycan markers as well as novel biopsy information. Refinement of technologies to analyse clinical biopsy material (yielding a glycotype for the tumour) in addition to serum glycans might assist with the rational choice and/or early application of glycan-based immunomodulators. Glycan analysis of serum or biopsy material could also facilitate the preoperative administration of tumour-glycan inhibitors to reduce the risk of operation-associated dissemination of microscopic tumour deposits. The recent application of microarray technology might provide insights into the array of enzymes and glycoproteins associated with the grade and stage of a given tumour. This, in turn, might indicate appropriate tumour and patient-specific panels of inhibitors to test. Valuable pharmacological approaches might then result from profiling drug design according to genetically validated targets.

As we continue to uncover clues about pathogenic mechanisms in tumour progression that glycans facilitate, or in some cases, govern, the integration of glycan-targeted therapy with existing cancer treatment protocols might have significant impact on disease outcomes. Progress so far on targeting complex carbohydrates in cancer (summarized in Table 3 ) might represent the 'tip of an iceberg' of therapeutic potential that awaits future discovery.


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