A plateau has been reached in the effectiveness of current treatments for cancer. Given that most major cancers remain refractory to therapy radically new approaches to preventing and treating cancer are clearly needed. To this end our approach is based on the fact that the distinguishing feature of a cancer cell compared to a normal cell is the presence in the cancer cell of mutated or overexpressed 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 deranged 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 our studies is to use oncogene-activated intracellular signalling pathways as targets for the rational development of novel chemotherapeutic and chemopreventive anticancer drugs. The signalling targets we will use include enzymes of phospholipid signalling (phosphatidylinositol phospholipase C, phosphatidylinositol-3-kinase and phospholipase D), protein serine/threonine kinases (Raf-1 kinase, MEK kinase and MAP-kinase) and enzymes that regulate the cell cycle (cdc25 phosphatase and Cdk4 kinase). We have developed multiwell plate high volume screening assays in addition to cell based secondary assays for each of these targets. The sources of compounds we will use for screening are Chinese traditional medicinal plant extracts, combinatorial natural product based progenomers and pure fermentation products. We will use bioassay targeted fingerprinting as a rapid way to identify active lead compounds. The active compounds we identify will be tested for their in vitro cytotoxicity against a panel of human tumor cell lines and the most active compounds will be tested for in vivo activity against a panel of transplanted murine and human tumors in mice. Preclinical development of promising lead compounds and high throughput screening of selected targets against a chemical library will be carried out by our commercial collaborator.
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