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 caus e greater than 75% of cancer deaths, remain incurable. Most drugs have been developed empirically by testing large numbers of chemicals on rapidly gro wing transplantable rodent tumors, and more recently, human tumor xenograft s. This approach has identified prodeminantly DNA-active drugs that are con siderably toxic and have limited efficacy. Novel molecular targets, which a re selective for neoplastic cells, are needed for chemotherapeutic agents t o improve cure rates of epithelial malignancies, with acceptable toxicity. In recent years, agents inhibiting signal transduction pathway molecules ha ve entered clinical trials. These include antibodies and small molecules, w hich inhibit growth factor receptors and their receptor tyrosine kinases, i nhibitors of cytoplasmic second messengers such as ras, raf and MEK, inhibi tors of protein trafficking, and inhibitors of protein degradation.