Discovery of novel thyrointegrin αvβ3 antagonist fb-PMT (NP751) in the management of human glioblastoma multiforme

Kavitha Godugu; Bruce A Hay; Gennadi V Glinsky; Shaker A Mousa

doi:10.1093/noajnl/vdac180

Discovery of novel thyrointegrin αvβ3 antagonist fb-PMT (NP751) in the management of human glioblastoma multiforme

Neurooncol Adv. 2022 Dec 8;5(1):vdac180. doi: 10.1093/noajnl/vdac180. eCollection 2023 Jan-Dec.

Authors

Kavitha Godugu¹, Bruce A Hay¹, Gennadi V Glinsky², Shaker A Mousa¹

Affiliations

¹ The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer & NanoPharmaceuticals LLC, Rensselaer, New York, USA.
² Institute of Engineering in Medicine, University of California, San Diego, La Jolla, California, USA.

Abstract

Background: Thyrointegrin αvβ3 receptors are unique molecular cancer therapeutic targets because of their 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 and 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.

Methods: The following in vitro assays were carried out to evaluate NP751 including binding affinity to different integrins, transthyretin (TTR)-binding affinity, glioblastoma multiforme (GBM) cell adhesion, proliferation assays, nuclear translocations, chorioallantoic membrane model of angiogenesis, and microarray for molecular mechanisms. Additionally, in vivo studies were carried out to evaluate the anticancer efficacy of NP751, its biodistribution, and brain GBM tumor versus plasma levels kinetics.

Results: NP751 demonstrated a broad spectrum of antiangiogenesis 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 < .001) in fb-PMT-treated U87-luc or 3 different primary human GBM xenograft-bearing mice based on tumor in vivo imaging system (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 tumors. NP751-induced effects on gene expression support the model of molecular interference at multiple key pathways essential for GBM tumor progression and vascularization.

Conclusions: fb-PMT is a potent thyrointegrin αvβ3 antagonist with potential impact on GBM tumor progression.

Keywords: antiangiogenesis; blood-brain barrier; gene expression profiling; glioblastoma; thyrointegrin αvβ3.