Small Molecule Targeting Stat3 Activity in Breast Cancer

Abstract

Researchers have discovered a small molecule that could be the first step in developing a new drug that may one day be able to treat multiple types of cancer.The study, published this week in the advanced online edition of the Proceedings of the National Academy of Sciences, identifies a small molecule that inhibits in cell cultures a protein involved in multiple types of cancer. The protein, called Stat3, is constantly activated in some but not all tumors and has been identified in breast cancer, prostate cancer, ovarian cancer and head and neck cancer. It contributes to new cancer cells growing and prevents cancer cells from dying. It's associated with poorer prognosis for patients since traditional chemotherapy treatments cannot shut down this protein.That's what makes it such an attractive target for new drug development, researchers say. In this new study, researchers at the University of Michigan Comprehensive Cancer Center discovered a molecule called STA-21 blocked Stat3 activity in human breast cancer cells, stopping cancer cells from growing and allowing them to die."We now can use this compound as a starting point to develop a new class of anti-cancer drugs to target cancer cells with constantly activated Stat3. One of the promises of molecular target drugs like this is they will work in many types of tumors where Stat3 protein is constantly activated. While our work looked specifically at breast cancer cells, there's a potential general application for other types of cancers with constantly activated Stat3," said study author Shaomeng Wang, Ph.D., associate professor of hematology/oncology at the U-M Medical School, assistant professor of medicinal chemistry at the U-M College of Pharmacy, and co-director of the Molecular Therapeutics Program at the U-M Comprehensive Cancer Center.Wang and his colleagues screened 3-D models of more than 400,000 small organic molecules using a computer program to search out structures most likely to bind to the Stat3 protein. This novel virtual screening strategy allowed the researchers to examine a large number of small molecules quickly and inexpensively. They identified 200 small molecules that appeared to match, and zeroed in on one, STA-21.When STA-21 was used in cultured breast cancer cells containing activated Stat3, the cancer cells began to die off. Cells from breast cancers without a constantly active Stat3 signal and non-cancerous cell lines were unaffected by STA-21.The research was a close collaboration between Wang's lab and Jiayuh Lin, Ph.D., formerly of the U-M Comprehensive Cancer Center and now an associate professor at the Ohio State University and member of the Ohio State University Comprehensive Cancer Center.Targeted molecular medicine is an exciting research approach to develop safer and more effective new anti-cancer drugs than conventional chemotherapeutic agents. Researchers hope targeting proteins specifically linked to cancer cells will lead to better, less toxic treatments that are tailored to each patient's particular cancer based upon its molecular signature."Stat3 is a very important protein involved in key processes in a number of different cancers. Up to 60 percent of human breast cancers may contain activated Stat3, and it may play an important role in both the growth and survival of these cells. The development of a specific inhibitor of Stat3 may therefore provide a novel therapeutic approach for breast cancer," said Max Wicha, M.D., director of the U-M Comprehensive Cancer Center.Researchers say their next step is to test STA-21 in animal models of human cancer to determine how effective STA-21 is in inhibition of tumor growth and to examine if STA-21 has any toxicity to animals. Wang also plans to work with the STA-21 compound to make it more potent and active, so it becomes an even more attractive candidate for drug development.In addition to Wang and Lin, study authors are Hui Song, a research associate in Lin's laboratory, and Renxiao Wang, a research investigator in Wang's laboratory, both at U-M.Funding for the study was provided by the U.S. Department of Defense Breast Cancer Research Program and from the National Institutes of Health. The National Cancer Institute provided the chemical sample of STA-21.Reference: Proceedings of the National Academy of Sciences, DOI .1073/pnas.0409894102