# Unique Non-Saccharide Mimetics of Sulfated Glycosaminoglycan Target Colon Cancer Stem Cells

> **NIH VA I01** · VA VETERANS ADMINISTRATION HOSPITAL · 2022 · —

## Abstract

This Collaborative VA Merit Application (CMA) leverages expertise of accomplished researchers who formed a
VA Colorectal Cancer (CRC) Cell-Genomics Consortium (VA4C) in May 2017. Cancer stem cells (CSCs) are
critical mediators of carcinogenesis and induce cancer relapse resulting in poor outcomes.
Glycosaminoglycans (GAGs), linear polysaccharides, that play a critical role in regulation of several hallmarks
of cancer, engage various cell surface receptor targets, especially on CSCs. Yet, their biological potential in
cancer has not been realized. Based on our highly intriguing recent observations that G2.2, a non-saccharide
glycosaminoglycan mimetic (NSGM) of a natural GAG, selectively inhibits CSCs through an oppositely-directed
mechanism involving growth factors, we propose that G2.2 is a novel, selective inhibitor of human CSCs. We
hypothesize that unique NSGMs can selectively and potently inhibit colorectal CSC growth through a novel
mechanism of antipodal pleiotropicity with respect to activation of growth factors. We propose three aims. We
will test the efficacy of G2.2 in 50 well characterized CSCs enriched primary human colorectal
spheroids/tumoroids as well as normal intestinal organoids, examine comprehensive CSC phenotype (self-
renewal, migration, invasion, and chemotherapy resistance), and determine pharmacokinetic profile of the
most promising NSGMs (Aim 1). In Aim 2, we will determine molecular mechanism of G2.2 (and analogs). We
will determine how antipodal pleiotropic effects arise, e.g., activation of fibroblast growth factor receptor
(FGFRs) and inhibition of insulin-like growth factor 1 receptor (IGF1R), and alter pp38/pERK signaling ratio,
which contributes to the CSC phenotype. Finally, in Aim 3, we will determine therapeutic utility of NSGMs in
vivo by examining efficacy (specifically on CSCs) and toxicity (effect on normal stem cells) in advanced in vivo
models of patient-derived xenografts (PDXs) or HT29 orthotopic xenografts either alone or in combination with
chemotherapy (5-fluorouracil & oxaliplatin). The proposed studies will be greatly enhanced by collaborative
merit process. Specifically, our collaboration with Drs. Mohapatra (Subhra)(Tampa), Raufman (Baltimore)
Pisegna (Greater LA) within our cluster of Cancer Stem Cells in Pathology and Treatment of CRCs (CSCPT),
as well as other VA4C collaborators including Mohapatra/Kelly (Tampa/Durham), and Dr. Bouvet (San Diego)
will allow – a) testing of NSGMs in novel tumoroid models for independent validation (Aim 1); b) decipher
predictive biomarkers for NSGM effect through correlation of effect with muti-omics studies; and c) testing of
NSGMs in novel animal models such as PDXs and distal colon orthotopic xenografts in Aim 3. Similarly, our
expertise and knowledge gained through the proposal will be shared with Drs. Mohapatra and Raufman (CSC
assays e.g. comprehensive analyses of CSC markers. CSC selectivity etc.), We will also assist other VA4C
investigators in collecti...

## Key facts

- **NIH application ID:** 10293533
- **Project number:** 5I01BX004584-02
- **Recipient organization:** VA VETERANS ADMINISTRATION HOSPITAL
- **Principal Investigator:** Bhaumik B Patel
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-10-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10293533

## Citation

> US National Institutes of Health, RePORTER application 10293533, Unique Non-Saccharide Mimetics of Sulfated Glycosaminoglycan Target Colon Cancer Stem Cells (5I01BX004584-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10293533. Licensed CC0.

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