Down-Modulation of Survivin Expression and Inhibition of Tumor Growth In Vivo by EZN-3042, A Locked Nucleic Acid Antisense Oligonucleotide

Abstract

Survivin plays an important role in preventing apoptosis and permitting mitosis, and is highly expressed in various human cancers. EZN-3042 is a locked nucleic acid antisense oligonucleotide (LNA-AsODN) against survivin. We report the effects of EZN-3042 in animal models. In a chemical-induced liver regeneration model, treatment with a mouse homolog of EZN-3042 resulted in 80% down-modulation of survivin mRNA. In A549 and Calu-6 lung xenograft models, treatment with EZN-3042 single agent induced 60% down-modulation of survivin mRNA in tumors and 37–45% tumor growth inhibition (TGI). In Calu-6 model, when EZN-3042 was combined with paclitaxel, an 83% TGI was obtained. EZN-3042 is currently being evaluated in a Phase 1 clinical trial as a single agent and in combination with docetaxel.

Keywords:

• Survivin
• locked nucleic acid
• antisense
• liver regeneration
• oligonucleotide
• mRNA

Acknowledgments

EZN-3042 is being developed by Enzon Pharmaceuticals, Inc., under a license with Santaris-Pharma A/S. We thank Jennifer Malaby and Mary Mileski for their help in performing animal studies.

All authors are full-time employees of Enzon Pharmaceuticals and own company's stock options and/or units.