XIAP antisense therapy with AEG 35156 in acute myeloid leukemia

Abstract

Introduction: AEG 35156 is an antisense oligonucleotide to X-linked inhibitor of apoptosis protein (XIAP). Overexpression of XIAP is common in acute myeloid leukemia (AML) and other cancers and is thought to cause resistance to cancer therapy. Effective treatment options for patients with relapsed or refractory AML are limited and survival continues to be poor. Targeting resistance mechanisms is expected to improve results in relapsed as well as front-line settings.

Areas covered: Role of XIAP in apoptosis pathways, structure of AEG 35156, mechanism of action, pharmacokinetics and pharmacodynamics, clinical efficacy and review of clinical trials in AML.

Expert opinion: AEG 35156 in combination with standard chemotherapy was generally very well-tolerated and had shown some evidence of anti-leukemic activity in AML. The target knock down was transient and has not always correlated with response. Future studies may be done with variations in dose scheduling and with more emphasis on comprehensive pharmacodynamic studies simultaneously analyzing other inhibitor of apoptosis proteins (IAPs) and various XIAP regulators. Use of small molecule mimetics of second mitochondria derived activator of caspases (Smac) simultaneously targeting other IAPs appears to be an attractive option.

Keywords::

• AEG 35156
• AML
• antisense oligonucleotide
• XIAP