Cold Spring Harbor Laboratory
Lab Website: http://vakoclab.labsites.cshl.edu/
Chemical inhibition of Brd9-SWI/SNF as a therapeutic approach in acute myeloid leukemia
In 2015, acute myeloid leukemia remains a deadly disease in most diagnosed patients and therefore new therapeutic strategies are desperately needed. An expanding body of evidence that has emerged over the past few years indicates that much of leukemia biology is epigenetic in nature, meaning that this disease is driven by the aberrant manner in which genes are turned “on” or “off” in cancer cells. Our research strategy seeks to exploit this principle by directly modifying leukemia biology using epigenetic therapies, which are drugs that modify the on/off state of genes. The backbone of our experimental approach has been the use of screening technology that allows us to discover epigenetic vulnerabilities present in any given cancer type. By applying this method to chemotherapy-resistant, lethal acute myeloid leukemia models, our laboratory has discovered two promising epigenetic drug targets for this disease. For one of these targets, called Brd4, we have shown that drugs targeting this pathway can extend the survival of leukemia-bearing mice with Brd4 inhibitors now under active investigation in Phase I/II clinical trials in leukemia. In this proposal, we outline research that seeks to advance a second drug target in this lethal disease, which is known as the SWI/SNF chromatinremodeling complex. Through a fruitful pharmaceutical collaboration, we have developed chemical matter that targets SWI/SNF to undermine the leukemia cell state. The proposed research will advance this new drug candidate as a potential leukemia therapeutic, with the objective of developing curative drug regimens that work via an epigenetic mechanism.