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The Path of Glycan-Based Biomarkers to Transform Cancer Diagnostics and Therapeutics

The quest to improve cancer diagnostics and therapeutics remains at the forefront of modern science, and glycoscience may hold the potential for groundbreaking progress. Why focus on glycoscience? Because changes in glycosylation—a fundamental post-translational modification—are closely associated with cancer progression. These glycosylation alterations often lead to unique glycan structures that can serve as reliable biomarkers for various cancers. Indeed, glycan-based biomarkers have been identified in several cancer types, including breast, ovarian, colorectal, prostate, pancreatic cancers, as well as lymphoma and myeloma, promising to enhance early detection and personalized treatment approaches.

But how close are we to fully implementing these findings to transform patient care? What advancements have already been made, and which techniques show the most promise? In this article, we delve into the current landscape of glycan-focused cancer diagnostics and therapeutics, spotlight two recent studies with compelling results, and share insights from Antoine Lesur, analytical scientist and Head of Analytics at Asparia Glycomics.

The Need for Standardization and Multidisciplinary Efforts

The well-established link between aberrant glycosylation and the initiation and progression of numerous cancers has propelled cancer glycomics research towards identifying specific glycan biomarkers. These biomarkers hold the potential to revolutionize cancer diagnosis and personalized treatment. Over the past few decades, efforts have largely focused on advancing technologies that allow the observation of large-scale glycosylation changes. Additionally, considerable progress has been made in connecting glycans to their protein carriers and exploring how these modifications impact intracellular signaling and cellular functions.

Despite these advancements, we are still at the early stages of fully deciphering glycosylation’s complex role in cancer. One of the critical challenges hindering successful biomarker discovery is the lack of standardized and accessible protocols for glycan sample preparation, data acquisition, and analysis. Therefore, collaborative efforts with experts across pertinent fields are essential. As Antoine Lesur emphasizes, «During the steps of biomarker discovery, verification, and validation, the choice of samples must be made in advance with the help of clinicians and statisticians to ensure that the data will be relevant.»

In addition, inter-subject variability studies should be integrated into glycan biomarker research. As outlined in our publication «Mass Spectrometry for Glycan Biomarker Discovery to ensure accuracy, any glycan biomarker study must include an analysis on variability between the genetic and demographic differences among individuals and due to specific pathological conditions.

Mass Spectrometry Techniques Driving the Present and Future

Various glycan analysis techniques can be applied to biomarker discovery, with mass spectrometry (MS) being an indispensable tool due to its precision in mass measurement for compositional analysis and its ability for structural identification.

For N- glycan analysis, a commonly employed MS technique is MALDI (matrix-assisted laser desorption/ionization), where a sample on a solid support can be combined with a matrix and undergo ionization. This technique is applied to the analysis of tissues of clinical samples in cancer.

For classic glycomics, it is also common to integrate complementary techniques. Mass spectrometry methods allow the possibility to couple with separation techniques like liquid chromatography, capillary electrophoresis and ion mobility. These combined techniques offer significant potential for separating isomers, which could be crucial for discovering new biomarkers. They are also regularly employed for quality control in biotherapeutics used in the treatment of cancer.

Breakthrough Studies of 2024 in Cancer Glycomics Research

In May of this year, researchers from Ivanov Lab at Northeastern University published a study in Nature Communications reporting unique results. They successfully applied capillary electrophoresis followed by mass spectrometry to analyze a single still-living human cell. Before this, nobody had examined, measured, and determined the structure of whole proteins and native glycans from an individual cell. This marked a relevant advanced towards diagnostics tests for a variety of diseases, including cancer.

Just a month later, a team from the Australian Institute for Bioengineering and Nanotechnology introduced another innovative technology in Advanced Science, that lead to significant results. They developed a nanodevice capable of analyzing glycopatterns of small extracellular vesicles (sEVs) released by lung cancer cells. In a clinical study of 40 patients, this nanotechnology distinguished early-stage malignant lung nodules from benign ones, demonstrating the potential of profiling small EV glycans for noninvasive lung cancer diagnostics and prognostics.

Tumor-Associated Carbohydrate Antigens: Potential Cancer Biomarkers

Among the diverse range of cancer biomarkers, Tumor-Associated Carbohydrate Antigens (TACAs) have drawn attention from researchers: «TACAs are glycan structures that are abnormally expressed in cancer cells. They play significant roles in tumor growth, metastasis, and immune evasion, which makes them potential biomarkers for cancer diagnosis and potential therapeutic targets», explains Antoine.

Some common TACAs are Thomsen-nouvelle antigen (Tn), sialyl Thomsen-nouvelle antigen (STn) and sialyl Lewis antigens. Tn and STn antigens have been identified in nearly all types of human carcinomas and are highly overexpressed in breast, colon, lung, pancreatic, and prostate cancers.

TACAs are commonly identified using chromatographic techniques combined with mass spectrometry. This process starts with extracting glycoproteins from serum or plasma, followed by purification involving antibodies or lectins, and then the glycans are detached from the peptide backbone through chemical or enzymatic treatments. Afterwards, the glycans are separated based on their structure polarity and size, allowing direct analysis via native MS.

Conclusions

Significant progress has been made with analytical techniques like mass spectrometry and the study of tumor-associated carbohydrate antigens (TACAs). However, challenges remain—particularly around standardization and the need for a stronger multidisciplinary approach.

To truly position glycoscience as a cornerstone of personalized medicine, greater investment, specialized expertise, and precision are essential. Asparia’s Glycan Analysis Service, led by Antoine Lesur, supports this vision by offering precise mapping of glycosylation patterns, enabling the accurate identification and synthesis of TACAs to propel your research and development forward.

References

  • Aizpurua-Olaizola, O., Toraño, J. S., Falcon-Perez, J. M., Williams, C., Reichardt, N., & Boons, G. J. (2018). Mass spectrometry for glycan biomarker discovery. TrAC Trends in Analytical Chemistry, 100, 7-14.
  • Doud, E. H., & Yeh, E. S. (2023). Mass spectrometry-based glycoproteomic workflows for cancer biomarker discovery. Technology in Cancer Research & Treatment22, 15330338221148811.
  • Marie, A. L., Gao, Y., & Ivanov, A. R. (2024). Native N-glycome profiling of single cells and ng-level blood isolates using label-free capillary electrophoresis-mass spectrometry. Nature Communications, 15(1), 3847.
  • Puiu, M., Nativi, C., & Bala, C. (2023). Early detection of tumour-associated antigens: Assessment of point-of-care electrochemical immunoassays. TrAC Trends in Analytical Chemistry, 160, 116981.
  • Zhou, Q., Niu, X., Zhang, Z., O’Byrne, K., Kulasinghe, A., Fielding, D., … & Trau, M. (2024). Glycan Profiling in Small Extracellular Vesicles with a SERS Microfluidic Biosensor Identifies Early Malignant Development in Lung Cancer. Advanced Science, 2401818.

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