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Published on: August 15, 2013
Lack of toxicity of a STAT3 decoy oligonucleotide
Malabika Sen1, Patricia J Tosca, Christa Zwayer
1Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Background:
STAT3 overexpression has been detected in several cancers including head and neck squamous cell carcinoma (HNSCC). Previous studies using intratumoral administration of a STAT3 decoy oligonucleotide that abrogates STAT3-mediated gene transcription in preclinical cancer models have demonstrated antitumor efficacy. This study was conducted to observe the toxicity and biologic effects of the STAT3 decoy in a non-human primate model, in anticipation of initiating a clinical trial in HNSCC patients.
Methods:
Three study groups (two monkeys/sex/group) were administered a single intramuscular injection of low dose of STAT3 decoy (0.8 mg total dose/monkey), high dose of STAT3 decoy (3.2 mg total dose/monkey) or vehicle control (PBS alone) on day 1 and necropsies were performed on days 2 and 15 (one monkey/sex/group/day). Low and high doses of the decoy were administered in the muscle in a volume of 0.9 ml. Tissue and blood were harvested for toxicology and biologic analyses.
Results:
Upon observation, the STAT3 decoy-treated animals exhibited behavior that was similar to the vehicle control group. Individual animal body weights remained within 1% of pretreatment weights throughout the study. Hematological parameters were not significantly different between the control and the treatment groups. Clinical chemistry fluctuations were considered within normal limits and were not attributed to the STAT3 decoy. Assessment of complement activation breakdown product (Bb) levels demonstrated no activation of the alternative pathway of complement in any animal at any dose level. At necropsy, there were no gross or microscopic findings attributed to STAT3 decoy in any organ examined. STAT3 target gene expression at the injection site revealed decreased Bcl-X(L) and cyclin D1 expression levels in the animals treated with high dose of STAT3 decoy compared to the animals injected with low dose of STAT3 decoy or the vehicle as control.
Conclusion:
Based on these findings, the no-observable-adverse-effect-level (NOAEL) was greater than 3.2 mg/kg when administered as a single dose to male and female Cynomolgus monkeys. Plans are underway to test the safety and biologic effects of intratumoral administration of the STAT3 decoy in HNSCC patients.
Insights
The STAT3 decoy oligonucleotide showed no observable adverse effects in non-human primates, supporting its potential use for head and neck cancer treatment. Further clinical trials are planned.
Area of Science:
- Oncology
- Molecular Biology
- Toxicology
Background:
- STAT3 overexpression is implicated in various cancers, including head and neck squamous cell carcinoma (HNSCC).
- Previous studies demonstrated antitumor efficacy of STAT3 decoy oligonucleotides in preclinical models.
- This study aimed to assess the safety and biological impact of the STAT3 decoy in a non-human primate model.
Purpose of the Study:
- To evaluate the toxicity and biological effects of a STAT3 decoy oligonucleotide.
- To establish a no-observable-adverse-effect-level (NOAEL) for the STAT3 decoy.
- To inform the design of future clinical trials for HNSCC patients.
Main Methods:
- Single intramuscular injections of low (0.8 mg) or high (3.2 mg) dose STAT3 decoy, or vehicle control, were administered to Cynomolgus monkeys.
- Toxicology and biological analyses were performed on blood and tissue samples.
- Necropsies were conducted on days 2 and 15 post-injection.
Main Results:
- No significant differences in behavior, body weight, hematology, or clinical chemistry were observed between treatment and control groups.
- No evidence of complement activation was detected.
- High-dose STAT3 decoy administration led to decreased expression of STAT3 target genes (Bcl-X(L), cyclin D1) at the injection site.
Conclusions:
- The no-observable-adverse-effect-level (NOAEL) for the STAT3 decoy was determined to be greater than 3.2 mg/kg in Cynomolgus monkeys.
- The STAT3 decoy demonstrated a favorable safety profile in this non-human primate study.
- Intratumoral administration of the STAT3 decoy is planned for HNSCC patients.
