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

Ohman, K. A., Hashim, Y. M., Vangveravong, S., Nywening, T. M., Cullinan, D. R., Goedegebuure, S. P., Liu, J., Van Tine, B. A., Tiriac, H., Tuveson, D. A., DeNardo, D. G., Spitzer, D., Mach, R. H., Hawkins, W. G. (June 2016) Conjugation to the sigma-2 ligand SV119 overcomes uptake blockade and converts dm-Erastin into a potent pancreatic cancer therapeutic. Oncotarget, 7 (23). pp. 33529-33541. ISSN 1949-2553 (Electronic)1949-2553 (Linking)

DOI: 10.18632/oncotarget.9551


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.

Item Type: Paper
Uncontrolled Keywords: erastin pancreatic cancer selective delivery sigma-2 receptors targeted therapy
Subjects: diseases & disorders > cancer > drugs and therapies
diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:
Communities: CSHL labs > Tuveson lab
CSHL Cancer Center Program > Cellular Communication in Cancer Program
Depositing User: Matt Covey
Date: 7 June 2016
Date Deposited: 10 Jun 2016 20:21
Last Modified: 26 Oct 2020 13:42
PMCID: PMC5085100
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