Targeting Anti-Apoptotic Proteins in Atypical Teratoid/Rhabdoid Tumors
Mentor: Jeffery Rubens
Atypical teratoid/rhabdoid tumors (AT/RT) are aggressive infantile brain tumors highly resistant to intensive therapies. We aim to identify and target critical factors driving this therapy resistance to improve AT/RT survival. Analysis of publicly available RNASeq on human biopsy and autopsy samples identified protective abnormalities in critical factors regulating the apoptotic cell death pathway in AT/RT. We design a novel combination of targeted therapies that we hypothesize will synergize to induce high rates of AT/RT cell death. PAC-1 circumvents the apoptotic signaling pathway to activate the ‘executioner caspase’ that transports to the nucleus and directly induces cell death. PAC-1 induced cell death is limited by XIAP, which is a protein that binds activated caspase and prevents its transport to the nucleus. LCL-161 is a small molecule inhibitor of XIAP. PAC-1 and LCL-161 have proven to be safe and to cross the blood-brain-barrier in previous clinical trials. Our preliminary data suggest that PAC-1 and LCL-161 act synergistically to induce high rates of cell death in AT/RT. In this POST award, Sepehr Akhtarkhavari will test the combination of therapy in our extensive collection of human-derived AT/RT cell models to determine their mechanisms of action, their impact on cell growth, cell cycle, and cell death. He will then expand his studies to orthotopic mouse models of AT/RT and evaluate how well the mice tolerate the therapy combination, the impact on tumor growth by bioluminescence imaging, and the impact on overall survival. These studies are aimed toward developing a new clinical trial to reduce therapy resistance and improve survival in AT/RT.
