Cancer is one of the leading causes of death in North America today. The Canadian Cancer Society estimates that in 2009 alone, 171,000 Canadians will be diagnosed. While there is no cure yet, a recent discovery at U of T Mississauga may give chemotherapy an added edge in the ongoing battle with this disease.

Patrick T. Gunning, professor in the Department of Chemical and Physical Sciences at UTM, is currently working with scientists at the University of Central Florida and Princess Margaret Hospital to improve the treatment of human cancers.

STAT3 (Signal Transducer and Activator of Transcription 3), a protein present in cancer cells, causes drug therapy resistance when it pairs up with another copy of itself. Gunning and his team have developed a way to break apart this cancer protein pair, to possibly increase the effectiveness of chemotherapy. His research team has successfully developed inhibitor molecules that work to stop STAT3 protein activity.

“We have managed to develop small molecules that target STAT3–STAT3 protein complexes” said Gunning. Targeting the protein-protein interactions of STAT3 disrupts the protein’s biological function.

Increased STAT3 activity is observed in multiple human cancers and plays a key role in cancer progression. In healthy individuals, STAT3 activity is transitory and highly regulated, lasting only a couple of minutes to a couple of hours. However, in cancer cells STAT3 is for some reason permanently activated, resulting in the expression of genes that promote cancer growth, survival, and differentiation.

Gunning’s research team is currently working to increase the stability and effectiveness of the STAT3 inhibitor molecules. “Our global objective is to develop novel molecular therapeutics to target human cancers. In particular, our research has focused on targeting protein-protein interactions—a particularly difficult medicinal challenge,” Gunning explained.

Traditional chemotherapy induces cell death in both healthy and cancerous cells, resulting in devastating side effects. Gunning’s preliminary STAT3 inhibitors display impressive selectivity for cancer cells over healthy cells, and hold promise for improving the effectiveness of chemotherapeutic techniques.

The team’s discovery highlights the importance and targetablity of protein-protein interactions. Gunning explained, “Despite the important role STAT3 plays in biological function, targeting protein–protein interactions is still regarded as high-risk. We want to illustrate through our molecular therapeutics that these important interactions are targetable and that a greater effort should be made on investigating them. STAT3 protein-protein interactions should be targeted because, if successful, the potential benefits are huge.”

Lead inhibitor compounds are now in pre-clinical trials. Gunning hopes that knocking out STAT3 will make cancer cells more susceptible to antineoplastics, thus reducing the dosage required and subsequently lowering the adverse side-effects associated with aggressive chemotherapy.

The results of this study can be found in the September issue of ChemBioChem: A European Journal of Chemical Biology.