Detection of Chemotherapy-resistant Pancreatic Cancer Using a Glycan Biomarker, sTRA

Abstract

Purpose: A subset of pancreatic ductal adenocarcinomas (PDACs) is highly resistant to systemic chemotherapy, but no markers are available in clinical settings to identify this subset. We hypothesized that a glycan biomarker for PDACs called sialylated tumor-related antigen (sTRA) could be used for this purpose. Experimental Design: We tested for differences between PDACs classified by glycan expression in multiple systems: sets of cell lines, organoids, and isogenic cell lines; primary tumors; and blood plasma from human subjects. Results: The sTRA-expressing models tended to have stem-like gene expression and the capacity for mesenchymal differentiation, in contrast to the nonexpressing models. The sTRA cell lines also had significantly increased resistance to seven different chemotherapeutics commonly used against pancreatic cancer. Patients with primary tumors that were positive for a gene expression classifier for sTRA received no statistically significant benefit from adjuvant chemotherapy, in contrast to those negative for the signature. In another cohort, based on direct measurements of sTRA in tissue microarrays, the patients who were high in sTRA again had no statistically significant benefit from adjuvant chemotherapy. Furthermore, a blood plasma test for the sTRA glycan identified the PDACs that showed rapid relapse following neoadjuvant chemotherapy. Conclusions: This research demonstrates that a glycan biomarker could have value to detect chemotherapy-resistant PDAC in clinical settings. This capability could aid in the development of stratified treatment plans and facilitate biomarker-guided trials targeting resistant PDAC.

Heterogeneity of Glycan Biomarker Clusters as an Indicator of Recurrence in Pancreatic Cancer

“…A plausible interpretation of the relationship found here is that CA19-9 and STRA in combination are markers of clonal heterogeneity of cancer cells. This interpretation concords with previous findings that the two glycans could identify both a stem-like founder population (marked by STRA) and another more-differentiated population (marked by CA19-9) (24). This link also concords with previous studies demonstrating the aggressive nature of clonal heterogeneity in tumors.…”

Breakthrough of glycobiology in the 21st century

“…The extraction of pesticides of animals origin (made up of lipids, waxes, and pigments) has been aided by column chromatography. The chromatography process is used in medicine to create the peptide hormone pramlintide (an analog of amylin), which is used to treat diabetes and many more (43).Various glycan detection technologies have shed light on the nature of several diseases, including COVID-19, diabetes, cancer, and congenital abnormalities (44)(45)(46).…”

The Current Treatment Paradigm for Pancreatic Ductal Adenocarcinoma and Barriers to Therapeutic Efficacy

“…Similarly, plasma levels of sTRA identified the PDACs that showed rapid relapse following neoadjuvant chemotherapy. Hence, pending further evaluation, sTRA may be a useful means of predicting for drug responses in PDAC patents (151).…”