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XIAP antisense therapy with AEG 35156 in acute myeloid leukemia
Lakshmikanth Katragadda1, Bing Z Carter, Gautam Borthakur
1MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Boulevard, Unit 428, Houston, Texas 77030, USA.
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.
Insights
AEG 35156, an antisense oligonucleotide targeting X-linked inhibitor of apoptosis protein (XIAP), showed anti-leukemic activity in acute myeloid leukemia (AML) when combined with chemotherapy. While generally well-tolerated, further studies are needed to optimize its use in AML treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- X-linked inhibitor of apoptosis protein (XIAP) overexpression is implicated in acute myeloid leukemia (AML) and cancer therapy resistance.
- Limited treatment options exist for relapsed or refractory AML, necessitating novel therapeutic strategies.
- Targeting cancer resistance mechanisms is crucial for improving patient outcomes in AML.
Purpose of the Study:
- To evaluate the role of XIAP in apoptosis pathways.
- To assess the clinical efficacy and safety of AEG 35156, an antisense oligonucleotide targeting XIAP, in AML patients.
- To review the pharmacokinetics, pharmacodynamics, and clinical trial data of AEG 35156 in AML.
Main Methods:
- Review of XIAP's role in apoptosis.
- Analysis of AEG 35156 structure and mechanism of action.
- Examination of clinical trial data for AEG 35156 in AML, including efficacy and safety.
Main Results:
- AEG 35156 in combination with standard chemotherapy demonstrated good tolerability in AML patients.
- Evidence of anti-leukemic activity was observed, although target knockdown was transient and not consistently correlated with response.
- Pharmacokinetic and pharmacodynamic properties were evaluated in clinical trials.
Conclusions:
- AEG 35156 shows potential as a therapeutic agent for AML when used with standard chemotherapy.
- Further research is warranted to optimize dosing and scheduling of AEG 35156.
- Combination therapies, including small molecule mimetics of second mitochondria derived activator of caspases (Smac), targeting multiple apoptosis inhibitors represent a promising future direction.
