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Lack of toxicity of a STAT3 decoy oligonucleotide

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Abstract

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-XL 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.

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Acknowledgment

This work was supported by the NCI RAID program, P50 CA097190, and R01 CA101840-01 (to JRG).

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Authors and Affiliations

  1. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Malabika Sen, Timothy P. McMurray, Michael S. Leibowitz, Robert L. Ferris, Sufi M. Thomas & Jennifer R. Grandis

  2. Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Daniel E. Johnson & Jennifer R. Grandis

  3. Battelle Toxicology, Columbus, OH, 43201, USA

    Patricia J. Tosca, Christa Zwayer, Michael J. Ryan, Jerry D. Johnson & Katherine A. B. Knostman

  4. Department of Immunology, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Michael S. Leibowitz & Robert L. Ferris

  5. Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    William E. Gooding

  6. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Changyou Li & Daniel E. Johnson

  7. National Jewish Medical and Research Center, Denver, CO, 80206, USA

    Patricia C. Giclas

  8. National Cancer Institute, Bethesda, MD, 20892, USA

    James O. Peggins & Joseph E. Tomaszewski

  9. Suite 500, Eye and Ear Institute, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA, 15213, USA

    Jennifer R. Grandis

  10. University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA

    Malabika Sen, Patricia J. Tosca, Christa Zwayer, Michael J. Ryan, Jerry D. Johnson, Katherine A. B. Knostman, Patricia C. Giclas, James O. Peggins, Joseph E. Tomaszewski, Timothy P. McMurray, Changyou Li, Michael S. Leibowitz, Robert L. Ferris, William E. Gooding, Sufi M. Thomas, Daniel E. Johnson & Jennifer R. Grandis

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  1. Malabika Sen
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  2. Patricia J. Tosca
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  5. Jerry D. Johnson
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  6. Katherine A. B. Knostman
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  7. Patricia C. Giclas
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  10. Timothy P. McMurray
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  11. Changyou Li
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  12. Michael S. Leibowitz
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  13. Robert L. Ferris
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  14. William E. Gooding
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  15. Sufi M. Thomas
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  16. Daniel E. Johnson
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  17. Jennifer R. Grandis
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Corresponding author

Correspondence to Jennifer R. Grandis.

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Sen, M., Tosca, P.J., Zwayer, C. et al. Lack of toxicity of a STAT3 decoy oligonucleotide. Cancer Chemother Pharmacol 63, 983–995 (2009). https://doi.org/10.1007/s00280-008-0823-6

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  • DOI: https://doi.org/10.1007/s00280-008-0823-6

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