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Cited by 313Cytokine Signaling Pathways and InteractionsRNA Interference and Gene DeliveryHead and Neck Cancer Studies

First-in-Human Trial of a STAT3 Decoy Oligonucleotide in Head and Neck Tumors: Implications for Cancer Therapy

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Sen, Malabika, Thomas, Sufi M., Kim, Seungwon, Yeh, Joanne I., Ferris, Robert L., Johnson, Jonas T., Duvvuri, Umamaheswar, Lee, Jessica +18 more·2012·Cancer Discovery
DOI 10.1158/2159-8290.cd-12-0191PMC PMC3668699

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Abstract

Despite evidence implicating transcription factors, including STAT3, in oncogenesis, these proteins have been regarded as “undruggable.” We developed a decoy targeting STAT3 and conducted a phase 0 trial. Expression levels of STAT3 target genes were decreased in head and neck cancers following injection with the STAT3 decoy compared with tumors receiving saline control. Decoys have not been amenable to systemic administration due to instability. To overcome this barrier, we linked the oligonucleotide strands using hexaethylene glycol spacers. This cyclic STAT3 decoy bound with high affinity to STAT3 protein, reduced cellular viability, and suppressed STAT3 target gene expression in cancer cells. Intravenous injection of the cyclic STAT3 decoy inhibited xenograft growth and downregulated STAT3 target genes in the tumors. These results provide the first demonstration of a successful strategy to inhibit tumor STAT3 signaling via systemic administration of a selective STAT3 inhibitor, thereby paving the way for broad clinical development. Significance: This is the first study of a STAT3-selective inhibitor in humans and the first evidence that a transcription factor decoy can be modified to enable systemic delivery. These findings have therapeutic implications beyond STAT3 to other “undruggable” targets in human cancers. Cancer Discov; 2(8); 694–705. ©2012 AACR. Read the Commentary on this article by Koppikar et al., p. 670. This article is highlighted in the In This Issue feature, p. 653.

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  • Systemic administration of the decoy in a murine xenograft model failed to demonstrate any effect on tumor growth or STAT3 signaling as a result of low stability of the decoy in serum.

    “Systemic administration of the decoy in a murine xenograft model failed to demonstrate any effect on tumor growth or STAT3 signaling as a result of low stability of the decoy in serum.”

    From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [100]

    The Results section reports that intravenous parental STAT3 decoy did not reduce xenograft tumor growth or downregulate STAT3 target genes. It also reports a short serum half-life, but describes degradation and/or thermal denaturation as a plausible explanation—not an established sole cause. Page numbers are unavailable in our copy. (LLM, conf=0.87)

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  • STAT3 is a druggable target in human tumors, as demonstrated by a Phase 0 clinical trial involving a STAT3 decoy oligonucleotide.

    “Indeed, a Phase 0 clinical trial involving a STAT3 decoy oligonucleotide demonstrated that STAT3 is a drug-gable target in human tumors.”

    From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [100]

  • A Phase 0 trial has demonstrated that STAT3 can be effectively targeted in human tumors.

    “Importantly, a Phase 0 trial has demonstrated that STAT3 can be effectively targeted in human tumors, and further preclinical studies have suggested that systemic delivery of STAT3 inhibitors is likely to be effective.100”

    From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [100]

  • Systemic administration by intravenous injection of the cyclic decoy in murine xenograft models inhibited tumor growth and expression of STAT3 target genes, demonstrating a successful strategy to inhibit intratumoral STAT3 signaling via systemic administration.

    “Importantly, systemic administration by intravenous injection of the cyclic decoy in murine xenograft models inhibited tumor growth and expression of STAT3 target genes, demonstrating a successful strategy to inhibit intratumoral STAT3 signaling via systemic, rather than intratumoral, administration.”

    From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [100]

  • Intratumoral injection of the STAT3 decoy prior to surgical resection in HNSCC patients led to decreased expression of STAT3 target genes relative to saline-injected tumors in a Phase 0 trial, confirming the ability of the decoy to downregulate STAT3 signaling in human tumors.

    “Intratumoral injection of this molecule prior to surgical resection in head and neck squamous cell carcinoma (HNSCC) patients led to decreased expression of STAT3 target genes relative to saline-injected tumors in a Phase 0 trial, confirming the ability of the decoy to downregulate STAT3 signaling in human tumors.”

    From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [100]

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References 44 · Cited by 313

Research works printed but not linked: 41

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Authors
Sen, M., Thomas, S. M., Kim, S., Yeh, J. I., Ferris, R. L., Johnson, J. T., Duvvuri, U., Lee, J., Sahu, N., Joyce, S., Freilino, M. L., Shi, H., Li, C., Ly, D., Rapireddy, S., Etter, J. P., Li, P.-K., Wang, L., Chiosea, S., Seethala, R. R., Gooding, W. E., Chen, X., Kaminski, N., Pandit, K., Johnson, D. E., & Grandis, J. R.
Affiliations
The University of Texas MD Anderson Cancer Center (US)
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2012-08-01
Volume
2
Issue
8
Pages
694-705
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-12-0191
PMC
PMC3668699
OpenAlex
W2135454149
Cited by
313
References
44
Citations by year
2026: 10 · 2025: 14 · 2024: 18 · 2023: 18 · 2022: 19 · 2021: 12 · 2020: 20 · 2019: 20 · 2018: 34 · 2017: 21 · 2016: 22 · 2015: 35 · 2014: 35 · 2013: 29 · 2012: 5
FWCI
16.46
Type
journal article
Language
en
Open access
Locations
  • Cancer Discovery (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Cancer Institute (R01CA137260, P50CA097190)
  • National Institute of General Medical Sciences (R01 GM082251, F32GM068566, P50GM082251, R01 GM068566)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Health Sciences › Medicine › Otorhinolaryngology › Head and Neck Cancer Studies
Keywords
STAT3, decoy oligonucleotides, head and neck cancer, transcription factor inhibition, undruggable targets, systemic drug delivery, xenograft tumor growth inhibition
MeSH terms
Animals, Female, Head and Neck Neoplasms, Humans, Male, Mice, Nude, Middle Aged, Random Allocation, Injections, Intralesional, Gene Expression, Oligonucleotides, Antisense, Xenograft Model Antitumor Assays, Cell Line, Tumor, STAT3 Transcription Factor, Mice

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