Mentor Name: Loren Walensky

The goal of the POST project is to test promising hits that emerged from a small molecule screen in biochemical and cellular assays aimed at validating direct activators of pro-apoptotic BAX as a next-generation cancer therapy for chemoresistant pediatric cancers. A major cause of drug resistance in pediatric cancer is the suppression of mitochondrial apoptosis due to the binding and sequestering of pro-apoptotic BAX by anti-apoptotic BCL-2 family proteins. Whereas strategies to block the anti-apoptotic grooves that mediate BAX interaction and blockade are well-developed, leading to the first small molecule inhibitor of anti-apoptotic BCL-2, drugs that target the “on switches” of cell death have lagged. The Walensky lab was the first to define the “trigger site” on BAX that unleashes its killing activity in response to natural ligands. Here, building on prior work funded by an Alex’s Million Mile grant, we will learn a series of functional assays to vet the promising BAX-interacting molecules for potent and on-target pro-apoptotic activity. Specifically, we will perform binding affinity, liposomal release, and cancer cell analyses as a rigorous workflow for characterizing direct BAX activator molecules. These results could inform the molecular features required to develop a drug that targets BAX in pediatric cancer cells to reactivate the apoptotic program, as a single agent or in synergistic combinations, for therapeutic benefit.