Abstract 4139: Development of a transcription factor decoy for efficient systemic administration in head and neck cancer

Abstract

Abstract This study was aimed to develop a transcription factor decoy for efficient systemic administration in head and neck cancer. Signal Transducer and Activator of Transcription-3 (STAT3) is upregulated in numerous human cancers including head and neck squamous cell carcinoma (HNSCC). Small molecules that target STAT3 are limited by lack of specificity. We developed a transcription factor decoy targeting STAT3 consisting of a 15-mer double-stranded oligonucleotide with three phosphorothioate modifications (PTO) at the 3′ and 5′ end of the double-stranded structure. This decoy exhibits antitumor efficacy in preclinical cancer models and is now being tested in a phase 0 human trial with intratumoral inoculation. To enable systemic administration, the STAT3 decoy formulation has been modified to enhance stability and uptake into tumors. A series of chemically modified STAT3 decoys have been designed to increase resistance to nucleases and enhance stability when administered in vivo. These include tetra-nucleotide single stranded DNA sequences (DN4), 18-atom hexa-ethyleneglycol spacers (DS18), and locked nucleic acid (LNA-1) modifications to enhance stability in serum. The modified STAT3 decoys were tested for serum nuclease degradation, melting temperature, binding to pSTAT3 protein, uptake and biologic activity. LNA-1 showed increased half-life of up to 8 h in serum, whereas DN4 is stable up to 4 h, DS18 up to 3 h compared with the parent STAT3 decoy, which is resistant only up to 2 h. The melting temperature demonstrated increased thermal stability for all the modified decoys compared to the parent STAT3 decoy. The DN4, DS18 and LNA-1 modified decoy bound to recombinant STAT3 protein as well as the parent decoy and inhibited head and neck cancer cell proliferation in vitro at nanomolar concentrations. The modified STAT3 decoys (DN4, DS18 and LNA-1) showed increased uptake into head and neck cancer cells similar compared with the parent STAT3 decoy. These modified decoys will be tested for their effect on STAT3 target gene expression and in vivo antitumor efficacy when administered systemically with anticipation of implementing a phase I clinical trial if tumor growth inhibition is observed upon intravenous injection. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4139.