Evaluation of STAT3 Antagonists in the Prevention of Mammary Cancer

A substantial body of preclinical data supports the validity of the JAK/STAT signaling pathway as a target for anticancer drug development. In spite of considerable skepticism regarding the targeting of transcription factors and protein-protein interactions, a variety of small-molecule inhibitors have been reported that target various aspects of the pathway. Demonstrated therapeutic activity of some of these agents in preclinical models generated sufficient interest for clinical development of an anti-sense agent (ISIS-STAT3Rx), a circularized oligonucleotide decoy molecule (STAT3 decoy) and a small-molecule inhibitor from Otsuka Pharmaceuticals (OPB-31121) for cancer treatment. The PREVENT program has previously evaluated GLG-302, a STAT3 dimerization inhibitor, in preclinical models of breast cancer. Results with GLG-302 demonstrated inhibition of pharmacodynamic biomarkers (pSTAT3, Cyclin D1, KI-67) in normal mammary ductal epithelium of mice and rats after oral administration and significant chemoprevention of mouse MMTV/Neu and rat DMBA-induced mammary tumors. Because of limited aqueous solubility and bioavailability, formulation development was conducted that yielded a stable salt form with improved physical and PK properties and that demonstrated preventive efficacy in the mouse model. While these studies provide proof-of-concept that STAT3 inhibition can have a chemopreventive effect towards mammary cancers, GLG-302 (even the salt form) does not appear to be an optimal candidate for clinical development. Other small molecule inhibitors have more recently become available that have improved potency, aqueous solubility and bioavailability. In this Task Order, two of these next generation compounds, with GLG-302 as a reference, will be evaluated and compared as candidates for further preclinical development as breast cancer chemopreventive agents.