Selective STAT3 Inhibitor Research Articles

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

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. This is the fi rst study of a STAT3-selective inhibitor in humans and the fi rst evidence that a transcription factor decoy can be modifi ed to enable systemic delivery. These findings have therapeutic implications beyond STAT3 to other “undruggable” targets in human cancers.

Involvement of the STAT3-Th17 axis in viral myocarditis induced by Coxsackievirus B3

ObjectiveThis study was designed to explore whether the STAT3-Th17 axis is involved in the pathology of viral myocarditis (VMC) induced by Coxsackievirus B3 (CVB3).MethodsWe induced VMC with male BALB/c mice...

Abstract 1983: A cell-permeable Stat3 SH2 domain mimetic inhibitor of Stat3 activation inhibits growth of human breast tumor xenografts

Abstract Human tumors harbor multiple molecular aberrations that have become the driving force for uncontrolled cell proliferation and survival, and other tumor-associated processes. Constitutive activation of the Signal Transducer and Activator of Transcription (Stat) 3 protein is a frequent occurrence in many human cancers, including breast cancer. Given the role of aberrant Stat3 activity in human tumors, small-molecule Stat3 inhibitors would be useful novel therapeutics and tools for probing Stat3-mediated tumor processes. We herein report that a 28-mer peptide, SPI, composed of the amino acid residues 588-615 of the Stat3 SH2 domain, replicates Stat3 biochemical properties and functions as a Stat3 inhibitor. Studies show SPI and Stat3 (or Stat3 SH2 domain) both bind with similar affinities to known Stat3-binding phosphotyrosine (pY) peptide motifs, including the epidermal growth factor receptor (EGFR) peptides, pY1068EGFR and pY1086EGFR, and the high-affinity, interleukin-6 receptor (IL-6R)/gp130-derived peptide, GpYLPQTV-NH2. Consequently, SPI potently and selectively inhibits Stat3 SH2 domain:pY interactions and disrupts the binding of Stat3 to the IL-6R/gp130 peptide, GpYLPQTV-NH2. Fluorescence imaging studies show SPI is cell membrane-permeable. Treatment with SPI of malignant cells that harbor aberrant Stat3 activity resulted in the selective inhibition of constitutive Stat3 phosphorylation, and of Stat3 DNA-binding and transcriptional activities. By contrast, similar treatments have little or no effects on the induction of the Stat1, Stat5, and Erk1/2MAPK pathways in malignant cells or in EGF-stimulated fibroblasts. In contrast to normal cells, human breast, pancreatic, prostate, and non-small cell lung cancer cells harboring constitutively-active Stat3 are highly sensitive to SPI and undergo extensive morphology changes, concomitant with the loss of viability and apoptosis. Significantly, treatment with SPI or its inverse sequence version strongly inhibited the growth of human breast tumor xenografts in mice, which is associated with the down-regulation of the expression of the known Stat3-regulated genes, Cyclin D1, Bcl-xL and Survivin. Our study identifies SPI as a novel molecular probe for interrogating Stat3 signaling and that functions as a selective Stat3 inhibitor, which induces antitumor response in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1983. doi:10.1158/1538-7445.AM2011-1983

Signal transducer and activator of transcription 3 inhibitors: a patent review

Importance of the field: Aberrant activation of signal transducer and activator of transcription (Stat) 3, a member of the STAT family of proteins, is prevalent in numerous human cancers and is now widely recognized as a critical molecular abnormality and a master regulator of tumor processes. Thus, the identification of potent and selective Stat3 inhibitors will have a high commercial potential as anticancer drugs, given the many tumors in which Stat3 is implicated.Areas covered in this review: This review covers the structures and activities of direct inhibitors of Stat3 protein activity described in the patent literature since the research field's inception in 2001. The patents reviewed include peptide and peptidomimetic compounds, small molecules, oligonucleotides and platinum-based Stat3 inhibitors.What the reader will gain: Readers will gain an understanding of how Stat3 protein function has been inhibited by a wide variety of structurally diverse therapeutic compounds. Readers will learn about which classes of patented Stat3 inhibitors are most advanced toward clinical trials, and will be exposed to the proposed mechanisms of inhibition and scope of their application in treating human cancers.Take home message: Numerous groups have shown that in vivo administration of inhibitors of activated Stat3 induce human tumor regression in xenograft models. Indeed, the growing number of preclinical studies in numerous cancer types, as well as the first Phase 0 clinical trial of a Stat3 inhibitor, suggest that Stat3 is a valid and exciting therapeutic target for molecular inhibitors.

Valproic Acid Selectively Inhibits STAT3 Phosphorylation.

Abstract 1720Poster Board I-746Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor (1), was found to enhance NK cell mediated antitumor activity by upregulating the surface expression of NKG2D ligands MICA and MICB on hepatoma cells (2). In contrast, VPA was found to impair NK cell antitumor activity by downregulating the surface expression of NKp30 and NKp46 on NK cells by blocking NFkB activation (3). Recently, we also found that VPA efficiently upregulates the surface expression of MICA, MICB, and ULBP family ligands on human osteosarcoma and neuroblastoma cells, but downregulates NKG2D surface expression on human NK cells. Similarly, the HDAC inhibitor MS275 efficiently upregulates expression of MICA, MICB, and ULBP family ligands on human osteosarcoma and neuroblastoma cells, but surprisingly, MS275 significantly upregulates NKG2D expression on NK cells. In addition, we found that VPA inhibited the cell growth of osteosarcoma cell lines more readily than MS275. To investigate the mechanism of these differing effects of VPA and MS275, we compared the effect of these HDAC inhibitors on Signal Transducer and Activator of Transcription (STAT) signaling, which are important signaling pathways in NK cells and many cancers. Here we show that VPA is a potent inhibitor of STAT3 phosphorylation at the tyrosine 705 residue in NK cells, whereas MS275 has no effect on STAT3 phosphorylation (Figure A). Moreover, this inhibition is highly specific, as VPA has no effect on STAT1 and STAT5 phosphorylation (Figure B). To further confirm VPA-mediated STAT3 inhibition, we detected STAT3 expression and the degree of tyrosine phosphorylation affected by VPA in a panel human osteosarcoma cells. We found that constitutive STAT3 phosphorylation is present in osteosarcoma SaOS2 and LM7 cells, but not in OS187 cells, which corresponded to the stronger growth inhibition caused by VPA in SaOS2 and LM7 cells compared to OS187 cells. These results are for the first to show that VPA, a HDAC inhibitor, is also a selective STAT3 inhibitor. VPA can upregulate NKG2D ligand expression on the tumor cell surface by HDAC inhibition, but may downregulate NKG2D expression on the NK cell surface by STAT3 inactivation. The antitumor activity of VPA may be via a mechanism of both HDAC inhibition and STAT3 inactivation. The knowledge of potent STAT3 inhibition by VPA is important for identifying potential new clinical applications for this drug. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Novel high-throughput screening system for identifying STAT3–SH2 antagonists

Constitutive activation of the oncogenic transcription factor STAT3 frequently occurs in various human malignancies. STAT3 activation involves dimerization via intermolecular pTyr–SH2 interaction. Thus, antagonizing this interaction is a feasible approach to inhibit STAT3 activation for cancer therapy. In order to identify selective STAT3 inhibitors, we developed a biochemical HTS system based on AlphaScreen technology, which measures the abilities of test compounds to antagonize pTyr–SH2 interactions. We screened our chemical libraries using this system and identified 5,15-diphenylporphyrin (5,15-DPP) as a selective STAT3–SH2 antagonist. Selective inhibition of STAT3 nuclear translocation and DNA biding activity was observed in cells treated with 5,15-DPP. IL-6-dependent dimerization of STAT3, c-myc promoter binding and c-myc protein expression were all suppressed by 5,15-DPP, whereas no decrement in either expression or phosphorylation level of STAT3 was observed. Thus, the HTS assay system represented herein may be useful for identifying novel STAT3–SH2 antagonists.