Pancreatic cancer remains almost incurable and has recently surpassed breast cancer as the third leading cause of death from malignant disease in the United States; an estimated 53,070 Americans will be diagnosed with pancreatic cancer and 41,780 will die from the disease this year (statistics from the Pancreatic Cancer Action Network). This project builds on two metabolic glycoengineering (MGE) approaches that our group has developed in previous funding periods for the parent R01 grant that reverse the disease-driving impact of two types of abnormal glycosylation broadly associated with cancer. One approach exploits our ?high flux? ManNAc analogs that increase sialylation, which masks galectin binding sites on highly-branched N-glycans and thereby attenuates ?galectin lattice? strength and reduces multiple aspects of cancer progression (our work focuses on EGFR but surveys a range of additional oncogenic surface markers). This approach will test the non-natural azide-modified form of ManNAc as a step towards developing theranostic treatment options where the sugar analog not only sensitizes drug resistant cancer cells to tyrosine kinase inhibitors (TKIs) but can also be used to image cancer using ?click chemistry? probes. In a complementary approach, we will use an alternative strategy to reduce cancer-driving glycosylation by inhibiting metabolic flux through the hexosamine biosynthetic pathway (HBP), which prevents the initial formation of the galectin lattice as well as knocking down other oncogenic glycoforms (for example, the ?O-GlcNAc? protein modification). This project will compare each of these approaches in cell lines that provide genetic diversity found in human patients (our expectation is that our ?glyco? approach will transcend genetic diversity and be broadly applicable) and then demonstrate efficacy in rodent models of pancreatic cancer using patient-derived cells and xenografts available to our team through the Johns Hopkins Medical Institute?s Division of Gastrointestinal and Liver Pathology (Dr. Anne Le, the co- investigator on this project is a faculty member of this division and has several years of experience conducting research with cell- and xenograft models of pancreatic cancer).
Pancreatic cancer remains almost incurable with less than a 2% 5-year survival rate for cases that are diagnosed at a late stage (which most are); overall this type of cancer has recently surpassed breast cancer as the 3rd most prevalent source of mortality from this disease. This project builds on our previous work where we showed that ?metabolic glycoengineering? can overcome drug-resistance in advanced stage pancreatic cancer cells. In the current grant period, we intend to demonstrate that this desirable feature holds across genetically diverse cases of pancreatic cancer and show that our therapeutic approach is viable in animal models as a prelude to clinical translation.
|Saeui, Christopher T; Liu, Lingshu; Urias, Esteban et al. (2018) Pharmacological, Physiochemical, and Drug-Relevant Biological Properties of Short Chain Fatty Acid Hexosamine Analogues Used in Metabolic Glycoengineering. Mol Pharm 15:705-720|
|Saeui, Christopher T; Nairn, Alison V; Galizzi, Melina et al. (2018) Integration of genetic and metabolic features related to sialic acid metabolism distinguishes human breast cell subtypes. PLoS One 13:e0195812|
|Buettner, Matthew J; Shah, Sagar R; Saeui, Christopher T et al. (2018) Improving Immunotherapy Through Glycodesign. Front Immunol 9:2485|
|Badr, Haitham A; AlSadek, Dina M M; El-Houseini, Motawa E et al. (2017) Harnessing cancer cell metabolism for theranostic applications using metabolic glycoengineering of sialic acid in breast cancer as a pioneering example. Biomaterials 116:158-173|
|Mathew, Mohit P; Tan, Elaine; Labonte, Jason W et al. (2017) Glycoengineering of Esterase Activity through Metabolic Flux-Based Modulation of Sialic Acid. Chembiochem 18:1204-1215|
|Mathew, Mohit P; Tan, Elaine; Saeui, Christopher T et al. (2016) Metabolic flux-driven sialylation alters internalization, recycling, and drug sensitivity of the epidermal growth factor receptor (EGFR) in SW1990 pancreatic cancer cells. Oncotarget 7:66491-66511|
|Bennun, Sandra V; Hizal, Deniz Baycin; Heffner, Kelley et al. (2016) Systems Glycobiology: Integrating Glycogenomics, Glycoproteomics, Glycomics, and Other 'Omics Data Sets to Characterize Cellular Glycosylation Processes. J Mol Biol 428:3337-3352|
|Toghi Eshghi, Shadi; Yang, Weiming; Hu, Yingwei et al. (2016) Classification of Tandem Mass Spectra for Identification of N- and O-linked Glycopeptides. Sci Rep 6:37189|
|Sun, Shisheng; Shah, Punit; Eshghi, Shadi Toghi et al. (2016) Comprehensive analysis of protein glycosylation by solid-phase extraction of N-linked glycans and glycosite-containing peptides. Nat Biotechnol 34:84-8|
|Yang, Weiming; Jackson, Brooks; Zhang, Hui (2016) Identification of glycoproteins associated with HIV latently infected cells using quantitative glycoproteomics. Proteomics 16:1872-80|
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