Clinical translation of angiogenesis inhibitors

Key Points Angiogenesis inhibitors are a relatively new class of cancer drugs. The biological and biochemical characteristics of angiogenesis inhibitors, however, differ from conventional cytotoxic chemotherapy. Basic research into the angiogenic process has revealed several ways by which the clinical efficacy of angiogenesis inhibitors can be improved. These include: Differentiating between direct and indirect angiogenesis inhibitors. Realizing that the microvascular endothelial cell is a genetically stable target of anti-angiogenic therapy. Understanding that slowly growing tumours, which are more difficult to treat by chemotherapy, respond well to anti-angiogenic therapy. An appreciation that rapidly growing tumours require higher doses of an angiogenesis inhibitor. Angiogenesis inhibitors are most effective when administered on a dose-schedule that maintains a constant concentration in the circulation instead of a schedule in which therapy is periodically discontinued. Chemotherapy seems to be angiogenesis dependent, in part, and a change in schedule to optimally target the endothelial cell instead of the tumour cell can overcome drug resistance in tumour-bearing mice. A current unsolved problem in anti-angiogenic therapy is the lack of surrogate markers for therapeutic efficacy. Whether quantification of circulating progenitor endothelial cells will become an indicator of efficacy remains to be shown. When various angiogenesis inhibitors become available for clinical use in cancer patients, these new therapeutic agents might be added to chemotherapy or to radiotherapy, or used in combination with immunotherapy or vaccine therapy. Angiogenesis inhibitors are a new class of drugs, for which the general rules involving conventional chemotherapy might not apply. The successful translation of angiogenesis inhibitors to clinical application depends partly on the transfer of expertise from scientists who are familiar with the biology of angiogenesis to clinicians. What are the most common questions that clinicians ask as they begin to test angiogenesis inhibitors in cancer clinical trials?