Discovery of Novel thyrointegrin αvβ3 Antagonist fb-PMT (NP751) in the management of human Glioblastoma Multiforme


 
 
 Thyrointegrin αvβ3 receptors are unique molecular cancer therapeutic target because of its overexpression on cancer and rapidly dividing blood vessel cells compared and quiescent on normal cells. A macromolecule, TriAzole Tetraiodothyroacetic acid (TAT) conjugated to Polyethylene glycol with a lipophilic 4-fluorobenyl group (fb-PMT, NP751), interacts with high affinity (0.21 nM) and specificity with the thyrointegrin αvβ3 receptors on the cell surface without nuclear translocation in contrast to the non-polymer conjugated TAT.
 
 
 
 The following in vitro assays were carried out to evaluate NP751 including binding affinity to different integrins, transthyretin (TTR)-binding affinity, GBM cell adhesion, proliferation assays, nuclear translocations, CAM model of angiogenesis, and microarray for molecular mechanisms. Additionally, in vivo studies were carried to evaluate anti-cancer efficacy of NP751, its biodistribution and brain GBM tumor versus plasma levels kinetics.
 
 
 
 NP751 demonstrated a broad spectrum anti-angiogenesis and anticancer efficacy in experimental models of angiogenesis and xenografts of human GBM cells. Tumor growth and cancer cells’ viability were markedly decreased (by > 90%; P <0.001) in fb-PMT-treated U87-Luc or three different primary human GBM xenograft-bearing mice based on tumor IVIS imaging and histopathological examination, without relapse upon treatment discontinuation. Additionally, it effectively transports across the blood brain barrier via its high affinity binding to plasma TTR with high retention in brain tumor. NP751-induced effects on gene expression support the model of molecular interference at multiple key pathways essential for GBM tumor progression and vascularization.
 
 
 
 fb-PMT is a potent thyrointegrin αvβ3 antagonist with potential impact on GBM tumor progression.
