Signal transduction pathway targets for anticancer drug discovery

There are currently over 80 agents officially approved for the treatment of cancer world-wide. However, the most common epithelial cancers, which cause greater than 75% of cancer deaths, remain incurable. Most drugs have been developed empirically by testing large numbers of chemicals on rapidly growing transplantable rodent tumors, and more recently, human tumor xenografts. This approach has identified prodeminantly DNA-active drugs that are considerably toxic and have limited efficacy. Novel molecular targets, which are selective for neoplastic cells, are needed for chemotherapeutic agents to improve cure rates of epithelial malignancies, with acceptable toxicity. In recent years, agents inhibiting signal transduction pathway molecules have entered clinical trials. These include antibodies and small molecules, which inhibit growth factor receptors and their receptor tyrosine kinases, inhibitors of cytoplasmic second messengers such as ras, raf and MEK, inhibitors of protein trafficking, and inhibitors of protein degradation.