The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in many critical biological processes, including cellular proliferation, cell cycle progression, viability, motility, invasion, neovascularization, and metastasis. Multiple components of the PI3K signaling cascade are aberrant in ovarian cancer at the DMA, RNA, and protein levels. These abnormalities in the PI3K pathway result in activation of the PI3K pathway in most ovarian cancers likely contributing to patient outcome. We have demonstrated that treatment with the PI3K inhibitor LY294002 markedly decreases cell proliferation, production of neovascularizing factors, motility, and invasion of ovarian cancer cells in vitro and growth, production of neovascularizing factors and neovascularization in xenografts in vivo. Further, overexpression of PI3K or AKT renders ovarian cancer cells resistant to the effects of paclitaxel, a major drug used in the management of ovarian cancer. Inhibition of PI3K sensitizes ovarian cancer cells to paclitaxel both in vitro and in vivo. LY294002 is, however, not a good pharmacophore and will not move forward clinically. Our previous studies suggest that catalytic inhibitors of AKT, which is downstream from PI3K, have a prohibitively narrow therapeutic index. Recently, we have demonstrated that two novel PI3K pathway inhibitors?perifosine, which blocks the PH domain of AKT, and SF1126, which is a pharmacologically optimized prodrug for the PI3K inhibitor LY294002?inhibit proliferation, production of neovascularizing factors, motility, and invasion and sensitize cells to paclitaxel in vitro. Perifosine markedly decreases growth of ovarian cancer cells in an orthotopic transplantation model. Based on our new data, we will pursue the following Specific Aims:
Aim 1 : To determine the efficacy of targeting PI3K with SF1126 and the PH domain of AKT with perifosine in ovarian cancer xenografts.
Aim 2 : To develop and validate methods to determine biologically relevant effective dose and markers of early therapeutic response that can be translated to clinical trials.
Aim 3 : To determine the efficacy of targeting ILK and PDK1 in ovarian cancer cells.
Aim 4 : To assess biologic and clinical activity in molecular pharmacodynamic clinical trials targeting the PI3K pathway
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