Summary

The practice of oncology has evolved from the use of cytotoxic compounds that nonselectively inhibit cells actively engaged in the cell cycle toward newer targeted agents that can block particular pathways important for neoplastic transformation, growth, and metastasis. The ultimate hope is that individualized drugs can induce tumor regression (or prevent progression) while avoiding the common toxicities attributed to conventional cytotoxic chemotherapy. Within the last 10 years, the approval of several targeted agents has led some to believe that our current system for drug development is adequate. Examples of such successes include the anti-HER-2/neu antibody trastuzumab in HER-2 overexpressing breast cancer; the c-Kit tyrosine kinase inhibitor imatinib in gastrointestinal stromal tumors (GISTs) and chronic myelogeneous leukemia; the epidermal growth factor receptor (EGFR) inhibitors erlotinib in lung cancer and cetuximab in colon cancer; the proteosome inhibitor bortezomib in multiple myeloma; and more recently the multitargeted tyrosine kinase inhibitors sorafenib in kidney cancer and sunitinib in kidney cancer and GISTs. However, this ignores the considerable costs in financial expenditures, large numbers of patients, and time required for the development of these agents. While the goal of drug development has remained the same (e.g., bring promising new drugs to the patients in need), for every 5000 compounds currently in preclinical development, only five agents enter clinical trials. The overall average cost of a drug approved by the Food and Drug Administration is≈$802 million (DiMasi et al., 2003). With the wealth of new agents being discovered, the current drug development paradigm is being challenged. It is clear that there are limitations in financial and human resources, and thus there is a demand for more efficient mechanisms of studying these newer drugs. For information related to this subject, see the chapter by Miller and colleagues in the first volume of this series.