Novel anticancer agents in clinical development.

There are currently more than 100 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 therapeutic agents 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 predominantly identified DNA-active drugs, which have limited efficacy and considerable toxicity. Novel agents, which selectively target aberrant elements in neoplastic cells and their microenvironment, are needed to improve the cure rates of epithelial malignancies. In recent years, advances in the understanding of molecular genetics and tumor biology have elucidated the molecular pathways implicated in the pathogenesis and progression of cancers and resulted in the discovery of a variety of novel molecular targets for therapeutic intervention. These targets can be conceptualized as supportive vessels, connective tissues, and signaling elements. Agents directed against these targets are those that interfere with signal transduction pathways, cell cycle regulation, and apoptosis (signals), malignant angiogenesis (vessels) and the tumor stroma (connective tissue). As anti-cancer therapeutics with distinct targeting capabilities against malignant cells become available for clinical evaluations, prioritization of these therapies for efficient allotment of clinical trial resources, identification of patients whose malignancies most likely express the molecular constituents resembling the true target, and derivation of relevant endpoints for both screening and assessment of clinical relevance will be critical to their ultimate development and success. This review will highlight promising rationally designed, target-based agents in clinical development, as well as the unique challenges involved in their successful development.