The target area to be studied in this proposal are the molecular targets provided by survival (anti-apoptosis) signaling pathways in cancer cells. The objectives of the study are to develop specific, sensitive and robust assays for the molecular target, to validate them in cellular and animal models, and to use the assays to measure drug effects on their targets in patient clinical trials. The targets we will study in Project 1 are 1) phosphatidylinositol-3- kinase (Ptdlns-3-kinase), an enzyme that phosphorylates membrane Ptdlns at the D-3-OH position of myo-inositol ring to give 3-phospho-Ptdlns. Ptdins-3-kinase is over expressed in a number of human cancers and t leads to increased proliferation and inhibition of apoptosis. The tumor suppresser PTEN, which is lost in a number of human tumors, antagonizes Ptdins-3-kinase signaling by dephosphorylating Ptdlns-3-phosphates. 2) A down stream target activated by Ptdlns-3-kinase is Akt (protein kinase B), itself an oncogene, that causes activation of a number of genes that inhibit apoptosis in cancer cells. Thus, Ptdins-3-kinase and Akt are important new anticancer drug targets on the same signaling pathway. We have identified the fungal metabolite wortmannin as a potent inhibitor of Ptdlns-3-kinase and an antitumor agent We have also identified 3-deoxy-phosphatidyl-myo-inositol ether lipid (DPIEL) as an inhibitor of the activation of Akt and an antitumor agent. Both drugs are currently undergoing preclinical development. The hypothesis, upon which our studies are based is that the inhibitors of Ptdins-3-kinase and Akt, wortmannin and DPIEL respectively, are promising new anticancer drugs that can be used to assess the usefulness of Ptdins-3-kinase and Akt as molecular cancer drug targets in animal models and in clinical trials in patients receiving these drugs. The goal of our studies is to provide a translational bridge between preclinical studies and clinical trials of molecularly targeted drugs and to develop more effective ways of preventing and treating cancer.
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