Project Background

Heparin and its derivatives are heterogeneous mixtures of glycosaminoglycans that have demonstrated promising anti-cancer properties in the treatment of blood and solid tumors, underpinned by their ability to disrupt the CXCL12/CXCR4 signaling axis. CXCL12-mediated activation of CXCR4-expressing cells within the tumor microenvironment leads to tumor progression and metastasis, chemoradiotherapy resistance, and cancer recurrence. Recent clinical studies have identified CXCL12 and CXCR4 as new therapeutic targets in treating locally advanced neck squamous cell carcinomas (HNSCCs) regardless of HPV status, reporting these molecules to be negative prognostic biomarkers for HNSCC locoregional control after surgery and chemoradiation. Due to their anti-coagulant activity and short half-life, daily subcutaneous or intravenous administration raises concerns about the safety profile and clinical utility of heparin and its derivatives as adjuvant cancer therapies. To address these shortcomings, we will synthesis and evaluate new, safe glycosaminoglycans based on sodium hyaluronate that exhibit potent inhibition of CXCL12/CXCR4-mediated cancer processes with controlled delivery in treating HNSCCs. Candidate drugs will first be synthesized and assessed for toxicity, anti-coagulant activity, and inhibition of CXCL12/CXCR4-mediated human HNSCC cell growth and invasion in vitro, and then optimized for controlled release from liposomal nanocarriers to reduce human HNSCC tumor growth ex vivo.

Student Role

Student Learning Outcomes and Benefits