Inhibitors of phospholipid intracellular signaling as antiproliferative agents.

The improved understanding of oncogenesis and the involvement of oncogenes and tumor suppressor genes, has led to a rational approach of specific target-directed anti-cancer drug development. Cancer genes have been found to be important not only in the control of cell proliferation but also in the mediation of processes such as drug resistance, metastasis, neo-vascularization (angiogenesis), and apoptosis. These are all important targets in their own right and the development of drugs against specific "upstream" targets in oncogenic or growth factor signal transduction cascades it may be possible to inhibit multiple "downstream" targets. Ultimately, to test the hypothesis that signaling pathways offer good targets for anticancer drug development will take several years of careful clinical study and we cannot say at this time whether the approach will work. There are a small number of compounds in the early stages of clinical development as anticancer agents that may act by inhibiting growth factor signaling pathways. In all cases the activity of the compounds on intracellular signaling pathways was discovered after their identification as antiproliferative agents. There are also compounds in preclinical development that have been specifically developed as inhibitors of growth factor signaling, although their selectivity for tumor cells compared to normal tissue remains to be investigated fully in appropriate animal tumor models. It is possible that a single antisignaling drug by itself may not have the power to completely inhibit tumor growth and a combination of drugs may be needed. It may also take a combination of drugs to prevent the emergence of resistance. Clearly there are several challenges to developing this new class of anticancer drugs, and there will undoubtedly be others that must be faced.