Development of molecular targeted anticancer agents: Successes, failures and future directions

Recent advances in molecular biology have identified numerous steps and proteins involved in malignant transformation as targets of anticancer therapy. Many molecular targeted agents are now undergoing clinical development. Successful developments of trastuzumab in treating breast cancer, imatinib in chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GISTs), and bevacizumab in colorectal cancer, have validated the concept of molecular targeting and raised expectations of patients and oncologists alike. Despite these successes, many agents, notably matrix metalloproteinase inhibitors (MMPIs), have failed in their development. In this review, we will address several issues related to tumor biology and clinical trial design that might have contributed to these successes and failures, and discuss strategies to best optimize the development of these novel agents.