Biomarkers of response and resistance to anti-angiogenic treatment

Over the last decade, anti-angiogenic therapy for cancer has become increasingly used as a standard therapeutic 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, there are currently no validated biological markers (or biomarkers) for appropriately selecting patients for anti-angiogenic therapy. Nor are there biomarkers identifying escape pathways that should be targeted after tumors develop resistance to a given anti-angiogenic drug. A number of potential systemic, circulating, tissue and imaging biomarkers have emerged from recently completed phase I/II/III studies of anti-angiogenic agents. Some of these are measured at baseline while others are measured during treatment - and all are mechanistically based. Some of these biomarkers may be pharmacodynamic, for example the increase in circulating VEGF and placental growth factor (PlGF). Others have potential for predicting clinical benefit or identifying the escape pathways, for example stromal-derived factor 1 alpha (SDF1α), interleukin 6 (IL-6) or angiopoietin 2 (Ang-2). Biomarkers of anti-angiogenesis may be disease and/or agent specific, and all of them need to be validated prospectively. In this chapter, I discuss the current challenges in establishing biomarkers of anti-angiogenic treatment. I also define the molecular and cellular biomarkers measured in blood circulation and tumor tissues, discuss their advantages and disadvantages, and comment on the future opportunities for validating biomarkers of anti-angiogenic therapy.