Safety and Efficacy of a STAT3-Targeted Cyclic Oligonucleotide: From Murine Models to a Phase I Clinical Trial in Pet Cats with Oral Cancer
STAT3 is an oncogenic transcription factor that activates both cancer cell signaling and induces an immunosuppressive immune environment, thus making it an attractive therapeutic target. Transcription factors have been considered “undruggable” and no STAT3 inhibitor has advanced beyond early clinical testing. We previously reported positive pharmacodynamics of a STAT3 decoy oligonucleotide administered intratumorally in a Phase 0 trial in patients with head and neck cancer squamous cell carcinoma (HNSCC). Here, we describe the anti-tumor and immune effects in immunocompetent preclinical HNSCC murine models and the safety and efficacy of systemically administered cyclic STAT3 decoy (CS3D) in a clinical trial in pet cats with HNSCC. Responders (35% of the cohort) showed significant differences in selected peripheral blood immune parameters as well as upregulation of PD-1 expression in the tumors compared with non-responders. These findings support a clinical trial of the CS3D in patients with cancers characterized by STAT3 activation. Overall design: RNA-seq profiling of oral cancer tumor biopsies from cats at Day 1 (pre-treatment) and on Day 8 prior to treatment with CS3D.