title: Conjugation to the sigma-2 ligand SV119 overcomes uptake blockade and converts dm-Erastin into a potent pancreatic cancer therapeutic.
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.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Kerri A
authors.initials: KA
authors.lastname: Ohman
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Yassar M
authors.initials: YM
authors.lastname: Hashim
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Suwanna
authors.initials: S
authors.lastname: Vangveravong
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Nywening
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Darren R
authors.initials: DR
authors.lastname: Cullinan
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.|Alvin J. Siteman Cancer Center, Barnes-Jewish Hospital, and Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: S Peter
authors.initials: SP
authors.lastname: Goedegebuure
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.|Division of Public Health Sciences, Section of Oncologic Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Alvin J. Siteman Cancer Center, Barnes-Jewish Hospital, and Washington University School of Medicine, St. Louis, MO, USA.|Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Van Tine
authors.affiliation: Cold Spring Harbor Laboratory, New York, NY, USA.
authors.forename: Herve
authors.initials: H
authors.lastname: Tiriac
authors.affiliation: Cold Spring Harbor Laboratory, New York, NY, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Tuveson
authors.affiliation: Alvin J. Siteman Cancer Center, Barnes-Jewish Hospital, and Washington University School of Medicine, St. Louis, MO, USA.|Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, USA.|Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: DeNardo
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.|Alvin J. Siteman Cancer Center, Barnes-Jewish Hospital, and Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Dirk
authors.initials: D
authors.lastname: Spitzer
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.|Alvin J. Siteman Cancer Center, Barnes-Jewish Hospital, and Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Hawkins
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010879:Piperazines / Q000494:pharmacology*; D017480:Receptors, sigma; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D053961:Azabicyclo Compounds; D002219:Carbamates; D008024:Ligands; D010879:Piperazines; D017480:Receptors, sigma; C579249:SV119; C477224:erastin; C106107:sigma-2 receptor
keywords: erastin; pancreatic cancer; selective delivery; sigma-2 receptors; targeted therapy