Translating STAT Inhibitors from the Lab to the Clinic

Oncogenic transcription factors represent unique and potentially high value targets for cancer therapy. Proteins like STAT3 and STAT5 are generally not mutated themselves. However, oncogenic signals arising from a wide array of upstream mutations and signaling events converge on a small number of these transcription factors to regulate expression of key genes involved in critical processes including proliferation, survival and invasion. While cancer cells frequently show a high dependency on continued activation of these proteins, normal cells are largely tolerant to interruption of these pathways due to redundancies in transcriptional regulators. Consequently, inhibition of STATs holds the potential to have a very high therapeutic index. The challenge has been to develop strategies to inhibit these proteins that lack domains that are easily amenable to antagonism by small molecules. In recent years, a number of promising strategies have emerged, and now clinical trials of approaches to directly inhibit activated STATs have been developed. The success of these studies, both in terms of clinical efficacy and understanding the molecular effects of STAT inhibitors in humans, may open a new front in the rational, targeted eradication of cancer.