This proposal aims to harness a novel type of senescence that we have identified in response to acute Pten inactivation, and which we believe offers a radical therapeutic approach to target the quiescent cancer stem cell in vivo. In characterizing Pten loss Induced Cellular Senescence, which we have named PICS for short, we have discovered that PICS is distinct from other forms of cellular senescence including oncogene-induced senescence (OIS) and replicative senescence. These distinct differences are characterized by a lack of DNA damage and hyper-replication, breaking the current dogma for senescence induction. The ability to induce senescence, an irreversible growth arrest, in cells by targeting Pten signaling, without a requirement for hyper-replication and DNA damage opens up the possibility to target quiescent cells, including stem cells, that have a low proliferative index. This approach has tremendous therapeutic potential and represents one of the most exciting developments for the advancement of prostate cancer therapy in recent years. Through the manipulation of senescence induction pathways we will identify PICS enhancing drugs and redefine the paradigm for cancer therapy. By developing novel mouse models that target prostate stem cells we will evaluate these PICS pro-senescence drugs in a pre-clinical setting. Finally, these results will be cross referenced with data from human prostate stem cells and we will lay the ground work to translate this to the clinical setting, further developing the clinical potential of these findings to eradicate prostate cancer.