A sensible approach to targeting STAT3-mediated transcription

Many cancers overexpress oncogenic proteins that drive robust tumorigenic signaling cascades which can be amenable to therapeutic targeting. However, inhibition of these proteins has been met with limited success to date, at least in part, due to the numerous feedback mechanisms driven by activation of alternative signaling pathways. To avoid the toxicities of targeting multiple receptors and oncogenic proteins, drug development focused on transcription factors is attractive. Transcription factors such as NF-κB, beta catenin and signal transducers and activators of transcription (STATs) are activated in the cytoplasm by numerous upstream signaling nodes before shuttling to the nucleus to drive transcription of mitogenic and antiapoptotic genes. Their ability to convey signaling from multiple oncogenic drivers and mediate gene expression makes them very promising therapeutic targets. An article published in November 2015 by Hong et al. in the journal Science Translational Medicine demonstrated that targeting the STAT family member STAT3 using an antisense oligonucleotide (ASO) AZD9150 resulted in potent and specific inhibition of STAT3 expression and suppression of lymphoma and lung cancer growth in preclinical models (1). They further observed antitumor activity with AZD9150 in a dose escalation study with 25 treatment-refractory patients