The Development of Novel Small Molecule Inhibitors of the Phosphoinositide- 3-Kinase Pathway through High-Throughput Cell-Based Screens

Abstract : The PTEN tumor suppressor gene is localized to the 10q23 interval and biallelic inactivation of PTEN has been demonstrated in prostate cancer cell lines, and in human primary and metastatic prostate cancers. In mice, inactivation of PTEN leads to prostate hyperplasia, PIN, and microinvasive cancers. Thus, PTEN is a bona fide tumor suppressor with special relevance to prostate cancer. We previously demonstrate that loss of PTEN protein was strongly associated with high-grade Gleason tumors and Suzuki et. al. showed that 56% of metastatic prostate cancer samples were PTEN null. Thus, loss of PTEN appears to correlate with clinical parameters known to be associated with poor outcome. These data suggest that small molecule inhibitors that act to reverse the transformed phenotype induced by loss of PTEN may find significant efficacy in lethal forms of prostate cancer. Loss of PTEN function leads to activation of the PI3K pathway, phosphorylation and activation of Akt and the subsequent aberrant phosphorylation and hence constitutive localization of the FOXO transcription factors to the cytloplasm of PTEN null cells. Based on these findings, we developed a novel, high-throughput cell-based screen using FKHR localization in PTEN null cells as a read-out. This screen has been conducted and numerous new lead compounds were identified. This grant focused on the evaluation of these lead molecules, their activity in in vitro and in vivo models, as well as their possible cooperation with other therapeutics targeting the same pathway.