Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a low cure rate and few therapeutic options. We recently discovered that approximately 50% of the pancreatic cancer cell lines tested in our lab (14 out of 31 lines) are highly sensitive to the selective BCL-XL inhibitor WEHI-539. Therefore, we will evaluate the potential efficacy of BCL-XL as a therapeutic target in PDAC both in vitro and in vivo. In addition, we will identify potential biomarkers of BCL-XL addiction, characterize mechanisms of sensitivity and resistance, and uncover novel drug combinations to further potentiate the activity of BCL-XL inhibitors in PDAC.
Pancreatic ductal adenocarcinoma (PDAC) is a commonly fatal malignancy whose treatment has changed only modestly in recent decades. We recently discovered that approximately half of the members of a large panel of cell lines derived from human PDAC patients are highly sensitive to an emerging class of drugs, selective BCL-XL inhibitors, setting the stage for the current proposal, in which we will evaluate the translational potential of BCL-XL inhibitors in both patient-derived and animal models of PDAC as well as leverage new genomic technologies developed in our lab to characterize the key mechanisms of resistance to this therapeutic strategy along with approaches to overcome resistance. These studies may lead to powerful new therapeutic approaches for PDAC
|Anderson, Grace R; Winter, Peter S; Lin, Kevin H et al. (2017) A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution. Cell Rep 20:999-1015|