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Preclinical characterization of AEG35156/GEM 640, a second-generation antisense oligonucleotide targeting X-linked
Eric C LaCasse1, Gabriele G Cherton-Horvat, Kimberley E Hewitt
1Aegera Therapeutics, Inc., Montreal, Quebec, Canada.
Purpose:
Cancer cells can use X-linked inhibitor of apoptosis (XIAP) to evade apoptotic cues, including chemotherapy. The antitumor potential of AEG35156, a novel second-generation antisense oligonucleotide directed toward XIAP, was assessed in human cancer models when given as a single agent and in combination with clinically relevant chemotherapeutics.
Experimental Design:
AEG35156 was characterized for its ability to cause dose-dependent reductions of XIAP mRNA and protein in vitro and in vivo, to sensitize cancer cell lines to death stimuli, and to exhibit antitumor activity in multiple human cancer xenograft models as a single agent or in combination with chemotherapy.
Results:
AEG35156 reduced XIAP mRNA levels with an EC50 of 8 to 32 nmol/L and decreased XIAP protein levels by >80%. Loss of XIAP protein correlated with increased sensitization to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in Panc-1 pancreatic carcinoma cells. AEG35156 exhibited potent antitumor activity relative to control oligonucleotides in three human cancer xenograft models (prostate, colon, and lung) and was capable of inducing complete tumor regression when combined with taxanes. Antitumor effects of AEG35156 correlated with suppression of tumor XIAP levels.
Conclusions:
AEG35156 reduces XIAP levels and sensitizes tumors to chemotherapy. AEG35156 is presently under clinical assessment in multiple phase I trials in cancer patients as a single agent and in combination with docetaxel in solid tumors or cytarabine/idarubicin in leukemia.
Insights
AEG35156, an antisense oligonucleotide targeting X-linked inhibitor of apoptosis (XIAP), effectively reduces XIAP levels in cancer cells. This enhances tumor cell sensitivity to chemotherapy, showing significant antitumor potential in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Cancer cells often evade apoptosis, a programmed cell death pathway, by upregulating proteins like X-linked inhibitor of apoptosis (XIAP).
- XIAP plays a crucial role in inhibiting caspases, thereby preventing cancer cells from undergoing apoptosis in response to various stimuli, including chemotherapy.
- Targeting XIAP presents a potential strategy to overcome chemoresistance and enhance antitumor efficacy.
Purpose of the Study:
- To evaluate the antitumor potential of AEG35156, a novel antisense oligonucleotide targeting XIAP.
- To assess AEG35156's efficacy as a single agent and in combination with standard chemotherapeutics in human cancer models.
Main Methods:
- AEG35156's ability to reduce XIAP mRNA and protein levels was characterized in vitro and in vivo.
- The study assessed AEG35156's capacity to sensitize cancer cell lines to apoptosis-inducing agents.
- Antitumor activity was evaluated in human cancer xenograft models, both as a single agent and in combination with chemotherapy.
Main Results:
- AEG35156 demonstrated dose-dependent reduction of XIAP mRNA and protein, with >80% decrease in protein levels.
- Loss of XIAP sensitized pancreatic cancer cells to TRAIL-mediated apoptosis.
- AEG35156 showed potent antitumor activity in prostate, colon, and lung cancer xenografts, leading to complete tumor regression when combined with taxanes.
Conclusions:
- AEG35156 effectively reduces XIAP levels, thereby sensitizing tumors to chemotherapy-induced apoptosis.
- The findings support AEG35156's potential as a therapeutic agent in various cancers.
- AEG35156 is currently under clinical investigation in Phase I trials for solid tumors and leukemia.
