The distinguishing feature of a cancer cell compared to a normal cell is the presence in the cancer cell of mutated or over-expressed oncogenes and the loss of tumor suppressor genes. The only known function of oncogenes is to code for proteins that are components of growth factor signalling pathways which causes the cancer cell to receive an unrestrained signal to grow. Thus, cancer can be considered a disease of altered intracellular signalling. Redundancy among intracellular signalling pathways allows selective inhibition of oncogene-activated pathways while leaving unaltered alternative pathways necessary for the normal functions of a cell. The objective of the applicant's studies is to test the hypothesis that targets on oncogene-activated intracellular signalling pathways provide rational sites for the development of new types of anticancer drugs and new approaches to treating cancer. He has identified several signalling targets for drug development and for each of these he has identified lead compounds as specific inhibitors. The targets he will study are: phosphatidylinositol-3- kinase, glycosylphosphatidylinositol phospholipases, phosphatidylinositol phospholipase C, and myoinositol phosphate-mediated Ca2+ signalling. He proposes to conduct mechanistic studies of each of these signalling targets using molecular and cell biology techniques to determine their role in cell growth and transformation. He will use the inhibitors to modulate the activity of these targets in experimental systems and relate inhibition of the target to inhibition of cell growth and antitumor activity. The goal of these studies is to determine if this new approach to anticancer drug development can provide more effective ways to treat cancer than those currently available.
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