A team of researchers at Virginia Commonwealth University Massey Cancer Center has discovered an entirely new mechanism of action for a novel pharmacological agent currently in clinical trials in patients – the kinase inhibitor BAY 43-9006 – which was designed to disrupt the survival pathways of tumor cells. “This agent was originally designed to inhibit the Raf-1 pathway, which is frequently mutated in many types of cancers, including leukemia,” said Steven Grant, M.D., Massey’s principal investigator for the study that was published in the Oct. 21 issue of the Journal of Biological Chemistry. BAY 43-9006 is a new agent known to induce apoptosis, or cell death, in a variety of tumor cells, presumably by interrupting this pathway. The agent was made available to Massey’s researchers by the National Cancer Institute.“We were surprised to find that the killing effects of Bay 43-9006 in human leukemia cells had very little to do with inhibition of the Raf-1 pathway,” Grant said. “Instead, the major mechanism of lethality of this compound involved down-regulation of a protein known as Mcl-1, which plays a critical role in protecting leukemic cells from apoptosis.“What was even more interesting was that Bay 43-9006 appeared to reduce Mcl-1 levels by an unusual and unexpected mechanism-inhibition of the initiation of protein synthesis,” Grant said. “This insight into the mode of action of Bay 43-9006 could have important implications for the development of rational combination strategies involving this agent in leukemia and potentially other types of cancer.”Grant is Massey’s associate director for translational research and co-leader of the cancer center’s cell-signaling program. He provides national leadership in hematologic malignancy research focused on finding new treatments for blood cancers such as leukemias, lymphomas and multiple myeloma. His work is funded by the National Cancer Institute, the V Foundation for Cancer Research, the Leukemia and Lymphoma Society of America and the Department of Defense.The first author on the published paper with Grant was Mohamed Rahmani, Ph.D., VCU department of internal medicine/hematology-oncology.
