Grant: Project Grant

Cancer is the leading cause of death in our country. The initial event for cancer formation involves mutations in the genetic material. In recent years, it has been increasing clear that mutations in key DNA repair enzymes such as PALB2 and BRCA2 contribute to genome instability, a hallmark of cancer. Although, increasing DNA damage in cancerous cells through radiotherapy or chemotherapy has been a useful strategy to treat cancer, these approaches have several drawbacks including secondary mutations in healthy cells. Hence, we need to design more clever and efficient approaches to kill cancer cells in the context of personalized medicine. Success for designing such personalized therapeutic strategies relies, however, on in-depth molecular understanding of the genetic abnormalities and thorough characterization of DSB repair mechanisms and their key enzymes. Thus, our research program is divided into the basic science study of DNA repair pathways and the investigation of strategies aimed at manipulating these pathways for a therapeutic benefit. The first two aims of this proposal will explore the poorly understood function of PALB2 and will shed light on the pathological outcomes of specific mutations found in this tumor suppressor. By knowing how PALB2 maintains the genome stable when the cells are dividing, we can design strategies to inhibit its function and sensitize cancer cells to DNA damaging agents. Hence, the third goal of the proposal will have a more immediate translational outcome. We will characterize novel synthetic lethal pathways and inhibitors of RAD52 to promote cancer cell killing of PALB2-deficient cells. Collaboration of several expert groups will permit us to efficiently conduct structure-activity relationship studies using biochemical methods, in vivo systems and combinatorial chemistry to develop novel drugs to improve treatment of breast cancer.