Signal Transducers and Activators of Transcription (STATs) are intracellular signaling proteins that are activated upon tyrosine phosphorylation and translocate from the cytosol to the nucleus where they bind to specific regions of DNA and exert transcriptional activity. STAT3 activation has been linked to transformation and tumor progression in several cancers, including squamous cell carcinoma of the head and neck (SCCHN). We have accumulated convincing evidence that constitutive STAT3 activation in SCCHN represents a critical survival pathway in SCCHN. We recently reported that activated STAT3 stimulated SCCHN growth independent of upstream growth factor receptors including EGFR. Further investigation demonstrated that activated STAT3 could be selectively targeted with a double stranded "decoy" oligodeoxynucleotide (ODN) representing the high affinity serum inducible element (hSIE). Blocking activated STAT3 with a STAT3 decoy inhibited SCCHN proliferation and STAT3-mediated gene expression with no effect on the growth of normal mucosal epithelial cells. Therefore, the overall aim of this proposal is to develop a therapeutic strategy that targets activated STAT3, thereby inhibiting SCCHN progression. A transcription factor decoy approach will be optimized to achieve maximal anti-tumor effects, with the ultimate goal of generating a formulation for efficient delivery to human SCCHN cells. To accomplish the goals of this proposal, we will: 1) determine the prognostic significance of activated STAT3 in SCCHN patients; 2) optimize the structure and delivery of the STAT3 decoy to enhance stability and maximize cellular uptake; 3) examine the anti-tumor effects of the STAT3 decoy; and 4) determine the toxicity and pharmacokinetics of optimized STAT3 decoy in preclinical animal models.