# Mechanism and Anti-Cancer Activity of SCFA-Hexosamine Analogs

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $350,016

## Abstract

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).

## Key facts

- **NIH application ID:** 10077209
- **Project number:** 5R01CA112314-13
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** KEVIN J YAREMA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $350,016
- **Award type:** 5
- **Project period:** 2005-09-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10077209

## Citation

> US National Institutes of Health, RePORTER application 10077209, Mechanism and Anti-Cancer Activity of SCFA-Hexosamine Analogs (5R01CA112314-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10077209. Licensed CC0.

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