Abstract
Cyclic STAT3 decoy (CS3D) is a second-generation, double-stranded oligodeoxynucleotide (ODN) that mimics a genomic response element for signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor. CS3D competitively inhibits STAT3 binding to target gene promoters, resulting in decreased expression of proteins that promote cellular proliferation and survival. Previous studies have demonstrated antitumor activity of CS3D in preclinical models of solid tumors. However, prior to entering human clinical trials, the efficiency of generating the CS3D molecule and its stability in biological fluids should be determined. CS3D is synthesized as a single-stranded ODN and must have its free ends ligated to generate the final cyclic form. In this study, we report a ligation efficiency of nearly 95 percent. The ligated CS3D demonstrated a half-life of 7.9 h in human serum, indicating adequate stability for intravenous delivery. These results provide requisite biochemical characterization of CS3D that will inform upcoming clinical trials.
Highlights
Signal transducer and activator of transcription 3 (STAT3) is a highly regulated transcription factor that plays a prominent role in cellular growth and survival, as well as inflammation [1,2]
Our results demonstrate that Cyclic STAT3 Decoy (CS3D) exhibits a roughly three-fold longer half-life in human serum compared to the first-generation linear STAT3 Decoy (S3D), an improvement that will facilitate more effective systemic delivery in humans
CS3D is initially synthesized as a unimolecular, single-stranded sequence
Summary
Signal transducer and activator of transcription 3 (STAT3) is a highly regulated transcription factor that plays a prominent role in cellular growth and survival, as well as inflammation [1,2]. AZD9150 has shown promise in early clinical trials, reducing tumor burden in patients with refractory lymphoma and non-small cell lung cancer [24] It is currently being evaluated as monotherapy in patients with advanced solid tumors and in combination with chemotherapy and/or durvalumab, an anti-PD-L1 monoclonal antibody (NCT: 03421353). A first-generation STAT3 decoy (S3D) was a linear double-stranded ODN, 15 base pairs in length with free ends. This linear S3D inhibits the growth of solid tumors in preclinical models and is well-tolerated in preclinical models [21,25,26,27,28,29]. Our results demonstrate that CS3D exhibits a roughly three-fold longer half-life in human serum compared to the first-generation linear S3D, an improvement that will facilitate more effective systemic delivery in humans
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