Work

Conjugation to the sigma-2 ligand SV119 overcomes uptake blockade and converts dm-Erastin into a potent pancreatic cancer therapeutic

Year: 2016

Type: article

Abstract: // Kerri A. Ohman 1,* , Yassar M. Hashim 1,* , Suwanna Vangveravong 2 , Timothy M. Nywening 1 , Darren R. Cullinan 1 , S. Peter Goedegebuure 1,3 , Jingxia Liu 1,4 , Brian A. Van Tine 3,5 , Herve Tiriac 6 , David A. Tuveson 6 , David G. DeNardo 3,5,7 , Dirk Spitzer 1,3 , Robert H. Mach 8 and William G. Hawkins 1,3 1 Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA 2 Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA 3 Alvin J. Siteman Cancer Center, Barnes-Jewish Hospital , and Washington University School of Medicine , St. Louis, MO, USA 4 Division of Public Health Sciences, Section of Oncologic Biostatistics, Washington University School of Medicine, St. Louis, MO, USA 5 Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA 6 Cold Spring Harbor Laboratory, New York, NY, USA 7 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA 8 Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA * These authors have contributed equally to the study Correspondence to: William G. Hawkins, email: // Keywords : sigma-2 receptors, erastin, pancreatic cancer, targeted therapy, selective delivery Received : March 01, 2016 Accepted : April 26, 2016 Published : May 22, 2016 Abstract Cancer-selective drug delivery is an important concept in improving treatment while minimizing off-site toxicities, and sigma-2 receptors, which are overexpressed in solid tumors, represent attractive pharmacologic targets. Select sigma-2 ligands have been shown to be rapidly internalized selectively into cancer cells while retaining the capacity to deliver small molecules as drug cargoes. We utilized the sigma-2-based drug delivery concept to convert Erastin, a clinically underperforming drug, into a potent pancreatic cancer therapeutic. The Erastin derivative des-methyl Erastin (dm-Erastin) was chemically linked to sigma-2 ligand SV119 to create SW V-49. Conjugation increased the killing capacity of dm-Erastin by nearly 35-fold in vitro and reduced the size of established tumors and doubled the median survival in syngeneic and patient-derived xenograft models when compared to non-targeted dm-Erastin. Mechanistic analyses demonstrated that cell death was associated with robust reactive oxygen species production and could be efficiently antagonized with antioxidants. Mass spectrometry was employed to demonstrate selective uptake into pancreatic cancer cells. Thus, targeted delivery of dm-Erastin via conjugation to the sigma-2 ligand SV119 produced efficient tumor control and prolonged animal survival with minimal off-target toxicities, and SW V-49 represents a promising new therapeutic with the potential to advance the fight against pancreatic cancer.

Source: Oncotarget

DOI: 10.18632/oncotarget.9551