Integrating molecular oncology into clinical practice: Antiangiogenic therapy

Although the process of angiogenesis in tumor progression and metastasis has been recognized for nearly 70 years, only recently have we been able to demonstrate that antiangiogenic therapy is of benefit to cancer patients. Targeted therapies are now becoming the basis of treatment for several neoplastic diseases, including breast carcinoma, leukemia, lymphoma, gastrointestinal stromal tumors, myeloma, lung cancer, and colorectal cancer. In 2004, the first antiangiogenic agent was approved by the US Food and Drug Administration for use in patients with metastatic colorectal cancer in combination with intravenous fluorouracil. The report by Hurwitz et al 1 was the first study to definitively demonstrate the superiority of an antiangiogenic agent combined with chemotherapy compared with chemotherapy alone in a randomized phase III clinical trial. The positive results of this study renewed enthusiasm in the field of antiangiogenic therapy, as previous clinical trials had not met the expectations of either oncologists or patients. In this first issue of the Journal of Clinical Oncology Molecular Oncology series, the focus is on angiogenesis and its role in the biology and therapy of cancer patients. Since vascular endothelial growth factor (VEGF) is the primary target for many antiangiogenic therapies, the issue starts with a Review Article on the biology of VEGF in tumor growth and angiogenesis. In this era of molecular therapy, a major goal of investigators is to translate findings from the laboratory into the clinic. Therefore, insightful preclinical studies that may provide the foundation for future clinical trials have also been included in this issue. In addition, the results from several early-phase and pilot clinical trials are reported to inform the reader of the status of antiangiogenic agents in various stages of development. It is important to note that several studies address the fact that certain agents and/or regimens may not be of benefit to specific patient populations. The reporting of negative studies is critically important, not only for selecting targeted therapies for future clinical trials, but also for elucidating the biology of specific angiogenic pathways and in designing more effective clinical trials. A second Review Article addresses the role of VEGF-directed therapy in renal cell carcinoma, where there is a great deal of promise based on phase II trial results using VEGF-targeted agents. Finally, we have included an additional Molecular Oncology Original Report that is representative of the types of papers that will be included in future issues of this series. It has become clear that angiogenesis is a much more complicated system than was originally believed, and that the induction of tumor dormancy by angiogenesis inhibition is only observed in a minority of patients undergoing such therapy. Understanding molecular mechanisms of angiogenesis and using a rational approach to targeted therapy should provide greater efficacy and clinical benefit to our patients. We must also understand that angiogenesis and maintenance of the vascular system occurs in physiologic systems and that one must be aware of the potential short-term and long-term adverse events that may occur in clinical trials targeting angiogenesis. We hope that this issue of the Journal of Clinical Oncology Molecular Oncology series provides reviews and original articles that are representative of the field and of interest to our readers.