Taken together, these preclinical studies provide lessons and promise for treating advanced stage PCa (including metastatic CRPC) with the hope that a combinatorial strategy for PI3K/AKT/mTOR, RAS/MAPK and/or STAT3 signal inhibition will impose a series of blockades that will impact the tumor-propagating ability and maintenance of PCSCs, thereby lowering PCSC burden by altering the dynamic balance, and subsequent conversion, between non-PCSC and PCSC pools. Here, AKT1 is linked to posterior cortical atrophy.