Targeted pancreatic cancer therapy with the small molecule drug conjugate SW IV-134.

Abstract

Pancreatic adenocarcinoma is highly resistant to conventional therapeutics and has been shown to evade apoptosis by deregulation of the X-linked and cellular inhibitors of apoptosis proteins (XIAP and cIAP). Second mitochondria-derived activator of caspases (Smac) induces and amplifies cell death by reversing the anti-apoptotic activity of IAPs. Thus, Smac-derived peptide analogues (peptidomimetics) have been developed and shown to represent promising cancer therapeutics. Sigma-2 receptors are overexpressed in many proliferating tumor cells including pancreatic cancer. Selected ligands to this receptor are rapidly internalized by cancer cells. These characteristics have made the sigma-2 receptor an attractive target for drug delivery because selective delivery to cancer cells has the potential to increase therapeutic efficacy while minimizing toxicity to normal tissues. Here, we describe the initial characterization of SW IV-134, a chemically linked drug conjugate between the sigma-2 ligand SW43 and the Smac mimetic SW IV-52 as a novel treatment option for pancreatic adenocarcinoma. The tumor killing characteristics of our dual-domain therapeutic SW IV-134 was far greater than either component in isolation or in an equimolar mix and suggests enhanced cellular delivery when chemically linked to the sigma-2 ligand. One of the key findings was that SW IV-134 retained target selectivity of the Smac cargo with the involvement of the NF-κB/TNFα signaling pathway. Importantly, SW IV-134 slowed tumor growth and improved survival in murine models of pancreatic cancer. Our data support further study of this novel therapeutic and this drug delivery strategy because it may eventually benefit patients with pancreatic cancer.

• Authors: Yassar M Hashim, Dirk Spitzer, Suwanna Vangveravong, Mary C Hornick, Gunjal Garg, John R Hornick, Peter Goedegebuure, Robert H Mach, William G Hawkins
• Journal: Molecular oncology (Mol Oncol) Vol. 8 Issue 5 Pg. 956-67 (Jul 2014) ISSN: 1878-0261 [Electronic] United States
• PMID: 24731702 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Azabicyclo Compounds
• Oligopeptides
• Receptors, sigma
• SW IV-134
• sigma-2 receptor
• Caspase 3

Topics

• Adenocarcinoma (drug therapy, metabolism, pathology)
• Animals
• Antineoplastic Agents (therapeutic use)
• Azabicyclo Compounds (therapeutic use)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Female
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Nude
• Molecular Targeted Therapy
• Oligopeptides (therapeutic use)
• Pancreas (drug effects, metabolism, pathology)
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Receptors, sigma (metabolism)