Pulling the plug on a cancer cell by eliminating XIAP with AEG35156.

Abstract

XIAP, the X-linked inhibitor of apoptosis, is the best example of an endogenous cellular suppressor of apoptosis. XIAP is effective because it directly limits the activity of several critical death-inducing caspases, notably caspase-3, -7 and -9, either by direct enzyme inhibition or through ubiquitin-mediated proteasomal degradation. Furthermore, XIAP acts simultaneously at several nodes in the apoptotic cascade, blocking both the intrinsic and extrinsic death pathways, and thereby preventing feed-forward amplification loops that would otherwise lead to cell death. XIAP over-expression, or increased activity, is associated with cancer progression, resistance to therapy and poor prognosis. Targeting XIAP gene expression by antisense oligonucleotides, or other approaches, demonstrates anti-cancer effects with XIAP down-regulation. These early preclinical studies led to the development of a clinical candidate mixed-backbone antisense oligonucleotide, AEG35156, against XIAP for the treatment of cancer. Published clinical results for the first-in-class and first-in-human trials of AEG35156 are summarized herein, including single agent and combination chemotherapy phase-I or -II trials for solid tumors, lymphoma, and acute myeloid leukemia. These trials demonstrate the safety of AEG35156, as well as some initial promising signs of anti-cancer activity.

• Authors: Eric C LaCasse
• Journal: Cancer letters (Cancer Lett) Vol. 332 Issue 2 Pg. 215-24 (May 28 2013) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 22776562 (Publication Type: Journal Article, Review)
• Copyright: Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• AEG 35156
• Oligonucleotides
• Oligonucleotides, Antisense
• X-Linked Inhibitor of Apoptosis Protein
• Caspases

Topics

• Animals
• Apoptosis
• Caspases (metabolism)
• Cell Survival
• Clinical Trials as Topic
• Disease Progression
• Down-Regulation
• Gene Expression Regulation, Neoplastic
• Humans
• Mice
• Neoplasms (drug therapy, genetics)
• Oligonucleotides (pharmacology)
• Oligonucleotides, Antisense (pharmacology)
• Prognosis
• Time Factors
• X-Linked Inhibitor of Apoptosis Protein (metabolism)