Periodic Reporting for period 1 - GlyCanDrug (A training network on the design of precision therapeutics that target key glycan motifs implicated in cancer)
Période du rapport: 2023-12-01 au 2025-11-30
Glycoscience, the interdisciplinary study of the structure, function, and biology of carbohydrates (or glycans) and their roles throughout biology, has made significant strides in the past decade, putting in the spotlight the key role of glycan-motifs on cancer glycocalyx (essentially a "sugar coat" surrounding tumor cells) in tumor-related events. It clearly emerged that targeting specific cancer associated glycan-motifs is key for overcoming cancer heterogeneity, opening new avenues for effective anti-tumoral therapeutics.
In this context, the MSCA-funded GlyCanDrug project is addressing this challenge, seeking to design precision therapeutics targeting specific cancer associated glycan-motifs, creating new opportunities for drug discovery. GlyCanDrug consortium is training 10 PhD students on innovative chemical strategies to suppress the role of cancer associated glycan-motifs in tumor progression. In particular, the PhD projects are focused on the development of small molecule inhibitors of target cancer-associated glycosyltransferases (GTs) and antibodies, produced with animal-free technologies, able to specifically recognize these glycan-motifs. The precise glycan-motif editing of cancer glycocalyx using selective inhibitors of cancer-associated glycosyltransferases (GTs) will pave the way for the development of novel precision therapeutics.
By the design and synthesis of GTs inhibitors, the development of high-throughput methodologies and specific cell-based assays for their screening, and the design and production of cancer-specific antibodies, the GlyCanDrug consortium is paving the ground to foster the creation of next generation cancer therapeutics.
In this context, the MSCA-funded GlyCanDrug project is addressing this challenge, seeking to design precision therapeutics targeting specific cancer associated glycan-motifs, creating new opportunities for drug discovery. GlyCanDrug consortium is training 10 PhD students on innovative chemical strategies to suppress the role of cancer associated glycan-motifs in tumor progression. In particular, the PhD projects are focused on the development of small molecule inhibitors of target cancer-associated glycosyltransferases (GTs) and antibodies, produced with animal-free technologies, able to specifically recognize these glycan-motifs. The precise glycan-motif editing of cancer glycocalyx using selective inhibitors of cancer-associated glycosyltransferases (GTs) will pave the way for the development of novel precision therapeutics.
By the design and synthesis of GTs inhibitors, the development of high-throughput methodologies and specific cell-based assays for their screening, and the design and production of cancer-specific antibodies, the GlyCanDrug consortium is paving the ground to foster the creation of next generation cancer therapeutics.
The GlyCanDrug research program focuses on two main activities:
- Activity 1: a precise inhibition of the expression of specific cancer-associated glycans thus affecting their functional role in cancer progression. With this in mind:
(1) Small molecule inhibitors of GTs are under development. Some of them have been screened on the bioanalytical assays which are already available within the consortium and show potent inhibition of selected GTs. Small molecule inhibitors are being assayed in cellular functional assays to validate hit molecules.
(2) An HTS microplate assay for the screening of sialyltransferases (STs) inhibitors has been already set up and published in open access.
(3) All the target GTs have been expressed in stable forms, and the validation of their catalytic activity is ongoing.
(4) Engineered cells for the screening of GTs inhibitors are under final validation.
- Activity 2: the development of cutting-edge tools that target those key cancer-associated glycans that are uniquely expressed on cancer cells. In particular, the preparation and validation of antibodies that target specific cancer-associated glycans are in the final step and the deliverable associated to this objective is foreseen in a couple of months.
- Activity 1: a precise inhibition of the expression of specific cancer-associated glycans thus affecting their functional role in cancer progression. With this in mind:
(1) Small molecule inhibitors of GTs are under development. Some of them have been screened on the bioanalytical assays which are already available within the consortium and show potent inhibition of selected GTs. Small molecule inhibitors are being assayed in cellular functional assays to validate hit molecules.
(2) An HTS microplate assay for the screening of sialyltransferases (STs) inhibitors has been already set up and published in open access.
(3) All the target GTs have been expressed in stable forms, and the validation of their catalytic activity is ongoing.
(4) Engineered cells for the screening of GTs inhibitors are under final validation.
- Activity 2: the development of cutting-edge tools that target those key cancer-associated glycans that are uniquely expressed on cancer cells. In particular, the preparation and validation of antibodies that target specific cancer-associated glycans are in the final step and the deliverable associated to this objective is foreseen in a couple of months.
GlyCanDrug consortium has generated scientific impact by the creation of new scientific knowledge in the development of novel strategies for the targeting of cancer-associated glycans. Results obtained so far enable us to overcome some limits in drug design of GTs inhibitors and beyond.
- Availability of target glycosyltransferases (GTs). These enzymes represent a remarkable tool for the whole scientific community, and their availability in pure and stable forms allows us to overcome the limit of drug discovery in this field.
- Availability of infrastructures for the fast screening of GTs inhibitors. Standardization framework: methods and protocols for the set-up of the HTS microplate assay for the screening of sialyltransferases inhibitors have been published in open access journal (https://doi.org/10.1002/cbic.202400539(s’ouvre dans une nouvelle fenêtre)) and are available to the scientific community. This result allows us to overcome the limit related to the fast screening of STs inhibitors.
- Creation of new scientific knowledge and state-of-the-art assessment. Four didactic review articles have been published in open access journals, bringing updated knowledge on glycioscience in cancer to the scientific community (https://doi.org/10.1021/jacsau.5c00716(s’ouvre dans une nouvelle fenêtre); https://doi.org/10.1111/febs.70079(s’ouvre dans une nouvelle fenêtre); https://doi.org/10.1016/j.drudis.2025.104507(s’ouvre dans une nouvelle fenêtre); https://doi.org/10.1038/s41467-025-66871-w(s’ouvre dans une nouvelle fenêtre)).
- Impact on the training of PhD students. GlyCanDrug demonstrates a strong commitment to mentoring and training doctoral candidates (DCs). Owing to the continuous and intense exchange of information with the non-academic partners and with international experts in translational research (i.e. Prof. Robert Sackstein), DCs are trained to appreciate the value of their research work in the context of market needs and other related employment sectors, such as hospitals and cancer treatment centers. In addition, through continuous discussions with representative scientists from different SMEs, they are learning key business and management skills to set up their own activity (e.g. a startup).
- Availability of target glycosyltransferases (GTs). These enzymes represent a remarkable tool for the whole scientific community, and their availability in pure and stable forms allows us to overcome the limit of drug discovery in this field.
- Availability of infrastructures for the fast screening of GTs inhibitors. Standardization framework: methods and protocols for the set-up of the HTS microplate assay for the screening of sialyltransferases inhibitors have been published in open access journal (https://doi.org/10.1002/cbic.202400539(s’ouvre dans une nouvelle fenêtre)) and are available to the scientific community. This result allows us to overcome the limit related to the fast screening of STs inhibitors.
- Creation of new scientific knowledge and state-of-the-art assessment. Four didactic review articles have been published in open access journals, bringing updated knowledge on glycioscience in cancer to the scientific community (https://doi.org/10.1021/jacsau.5c00716(s’ouvre dans une nouvelle fenêtre); https://doi.org/10.1111/febs.70079(s’ouvre dans une nouvelle fenêtre); https://doi.org/10.1016/j.drudis.2025.104507(s’ouvre dans une nouvelle fenêtre); https://doi.org/10.1038/s41467-025-66871-w(s’ouvre dans une nouvelle fenêtre)).
- Impact on the training of PhD students. GlyCanDrug demonstrates a strong commitment to mentoring and training doctoral candidates (DCs). Owing to the continuous and intense exchange of information with the non-academic partners and with international experts in translational research (i.e. Prof. Robert Sackstein), DCs are trained to appreciate the value of their research work in the context of market needs and other related employment sectors, such as hospitals and cancer treatment centers. In addition, through continuous discussions with representative scientists from different SMEs, they are learning key business and management skills to set up their own activity (e.g. a startup).