Ten antiangiogenic medications targeting VEGF or its receptors are approved for malignancy treatment. antiangiogenic therapy outcomes for malignant and nonmalignant diseases. SL 0101-1 Introduction Tumors acquire blood supply via multiple mechanisms: angiogenesis (sprouting new vessels from existing vessels) co-option intussusception vasculogenesis vascular mimicry and trans-differentiation of malignancy cells into endothelial cells (Carmeliet and Jain 2011 More than 40 molecules have been recognized to play a critical role in blood vessel recruitment but most studies to date have focused on VEGF and its receptors. In fact since 2004 10 drugs that target VEGF or its receptors SL 0101-1 have been approved for the treatment of various malignant diseases (Table 1) with many more in clinical trials. Regrettably these brokers – used as monotherapy or in combination with chemotherapy – have only provided survival benefits on the order of weeks to months in some tumor types and have not been efficacious at all in others. Multiple mechanisms underlie these incremental benefits. In this Perspective I will discuss these mechanisms and speculate on how we can better utilize current antiangiogenic (AA) brokers and develop new ones to improve benefit to patients with malignancy or other diseases with abnormal SL 0101-1 vasculature. Instead of reviewing the entire literature I will focus on the underlying principles – inspired by the works of many in this field but relying greatly on insights gained from our own pre-clinical and clinical studies. Table 1 Survival Benefits from Anti-VEGF/VEGFR Drugs Solid tumors develop resistance to targeted therapies including AA therapies Millions of advanced malignancy patients worldwide have benefited from molecularly targeted therapeutics – whether these brokers target oncogenic pathways in malignancy cells angiogenic pathways in blood vessels or both. However some tumors are intrinsically resistant to these brokers while others develop resistance after an initial response thus limiting overall survival benefits to months (Table 1). An important feature that distinguishes the AA drugs from other targeted therapies is that AA brokers are typically given to patients for the approved indications whereas malignancy cell targeted therapeutics are given to only subsets of patients on the basis of biomarkers. Thus informed selection of patients likely to benefit from AA drugs could significantly improve benefits from these brokers. For example recent studies show that recurrent and newly diagnosed glioblastoma (GBM) SL 0101-1 patients whose tumor blood perfusion or oxygenation increases after the initiation of AA therapy survive 6-9 months longer than those whose tumor perfusion does not switch or instead decreases (Batchelor et al. 2013 Emblem et al. 2013 Sorensen et al. 2012 These emerging data suggest that we should be able to improve overall survival with a more personalized use of existing AA brokers and Igf2r by developing novel hypoxia-alleviating brokers. Why alleviating hypoxia is critical for improving malignancy treatment The imbalance between pro- and anti-angiogenic signaling as well as physical compression leads to abnormal vessels and impaired blood perfusion in tumors (Jain 2005; Jain 2013). The degree of blood flow impairment varies with tumor growth stage and location and can differ among tumor regions (Movie S1 SL 0101-1 embedded in Physique 1) or between a primary tumor and its metastases. This progressively worsening heterogeneity in blood perfusion as tumors grow raises an interesting conundrum: if a tumor needs blood vessels to grow and to metastasize how does it keep growing when growth impairs the very blood supply that brings the required nutrients and removes waste products? This apparent paradox can be comprehended by thinking about how reduced blood supply can impart a survival advantage to these renegade cells by creating an abnormal microenvironment characterized by hypoxia and acidosis (Physique 1). Physique 1 Hypoxia and acidosis resulting from impaired perfusion gas tumor progression and treatment resistance Our hypothesis is that impaired blood supply and the producing abnormal tumor microenvironment help malignancy cells evade the immune system increase their invasive and.