Antiangiogenic therapy for cancer has gone from an intriguing hypothesis in the 1970s to an accepted treatment approach for many cancer types. It has also become a standard of care for certain eye diseases. Yet, despite the use of molecularly targeted drugs with well defined targets, to date there are no biomarkers to guide the use of antiangiogenic therapy in patients. The mechanisms of action of these drugs are also being debated. This paper discusses some of the emerging biomarker candidates for this type of cancer therapy, which have provided mechanistic insight and might be useful in the future for optimizing cancer treatment. 1. Antiangiogenic Therapy Approval of an anti-vascular endothelial growth factor (VEGF) blocking antibody (bevacizumab or Avastin, Genentech, South San Francisco, CA, USA) in combination with chemotherapy for metastatic colorectal cancer in 2004 represented a paradigm shift in cancer therapy. For the first time, an agent targeting the tumor stroma (i.e., the vasculature), as opposed to directly targeting the malignant cells proved to be a viable anticancer treatment option. Over the last decade, the United States Food and Drug Administration has approved eight anti-angiogenic agents for cancer treatment, and three anti-angiogenic agents for wet age-related macula degeneration therapy (Table 1). A large number of other anti-angiogenic agents are in late phases of clinical development (phase III clinical trials). All the approved anti-angiogenic drugs target VEGF signaling. Some are blocking the ligand, VEGF, for example, bevacizumab, aflibercept (Zaltrap/Eylea, Sanofi-Aventis, Paris, France, and Regeneron Pharmaceuticals, Tarrytown, NY, USA), ranibizumab (Lucentis, Genentech, South San Francisco, CA, USA), and pegaptanib (Macugen, OSI Pharmaceuticals, Long Island, NY, USA). Others are inhibiting the activity of the VEGF tyrosine kinase receptors (VEGFR1, VEGFR2), for example, sorafenib and regorafenib (Nexavar and Stivarga, Bayer Healthcare Pharmaceuticals, Leverkusen, Germany, and Onyx Pharmaceuticals, South San Francisco, CA, USA), sunitinib (Sutent) and axitinib (Inlyta) (Pfizer Inc., New York, NY, USA), pazopanib (Votrient, GlaxoSmithKline, Brentford, Middlesex, UK), and vandetanib (Zactima, Astra Zeneca Pharmaceuticals, Alderley Park, Cheshire, UK). Anti-VEGF therapy has become a standard of care for metastatic colo-rectal cancer (in first, second, and third line of treatment), advanced non-small cell lung cancer, renal cell carcinoma, hepatocellular carcinomas, glioblastoma, gastrointestinal stromal tumor (GIST),
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