Umesh Desai

Virginia Commonwealth University, USA

Title: Discovery and Mechanism of Action of Highly Selective Anti-Cancer Stem Cell Agents

Biography

Umesh Desai is the Alfred Burger Professor of Medicinal and Biological Chemistry at Virginia Commonwealth University (VCU), Richmond, VA. He also serves as the Chair of the Department of Medicinal Chemistry in the School of Pharmacy at VCU. He received his baccalaureate from the M. S. University of Baroda, and his doctorate from the Indian Institute of Technology, Bombay, India. Following postdoctoral and senior researcher experiences at University of Iowa, Massachusetts Institute of Technology, and University of Illinois, Chicago, he moved to VCU in 1998 where he has risen through the ranks to full professorship. He specializes in rational drug design with emphasis on glycosaminoglycan-based agents that function as anticoagulants and anticancer agents. He received an Established Investigator Award from the American Heart Association (2006) and Distinguished Scholarship Award from VCU (2013).

Abstract

Glycosaminoglycans (GAGs), such as heparan sulfate (HS), have been implicated in tumorigenic responses including initiation, progression, metastasis, and angiogenesis. We have shown that a defined 6-mer of HS, but not 4-, 8-mer or longer, inhibits colorectal cancer stem cells (CSCs) by inducing activation of p38 MAPK. Our recent work demonstrates that a synthetic mimetic of the HS 6-mer, labeled as G2.2, selectively targets CSCs over bulk adherent tumor cells. We now report a hypothesis-driven analog design to discover three lipid-modified G2.2 analogs. Microarray-based screening against more than a dozen receptor tyrosine kinases led to identification of IGF-1R as a potential receptor of the synthetic GAG mimetics. Biophysical studies indicated that the preferred soluble and/or cell surface target receptors were in line with microarray results. Interestingly, G2.2 preferentially bound to IGF-1R in comparison to its soluble ligand IGF-1. G2.2 also preferred IGF-1R over an alternative receptor FGFR-1. The lipid-modified analogs bound to IGF-1R with better affinities as compared to parent mimetic G2.2, which support the cell-based anti-CSC inhibition results. Three different models of CSC growth in mouse were performed to test the efficacy of the lipid-modified analogs in vivo. Two of the lipid-modified analogs G2C and G5C were found to selectively inhibit CSCs in vivo and reduce tumor progression better than a combination of 5-fluorouracil and oxaliplatin (FUOX). Additionally, G2C and G5C displayed oral bioavailability and in vivo anti-cancer activity. Overall, this work presents a powerful proof of concept that synthetic GAG mimetics are unique anti-cancer therapeutics with high potential for selective elimination of the tumor initiating cells.