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Antiangiogenics and Hypoxic Response: Role of Fatty Acid Synthase Inhibitors.

One proposed mechanism through which antiangiogenics exert their effect in epithelial malignancies is by improving the status of the aberrant vascular network and secondarily facilitating the delivery of concurrently administrated cytotoxic agents. During this process, known as vascular normalization, the oxygenation of the tumor is usually improved. Many mechanisms of resistance have been proposed to evade the action of this drug class elicited through this mechanism of action. However, a less explored mechanism of action is vascular choking, as increased hypoxia is thought to be associated with the inevitable progression of certain tumor-promotion features. Here we review the available evidence regarding decreased blood flow as a mechanism of action of antiangiogenics at the preclinical and clinical level. Similar to vascular normalization, there are also escape mechanisms against chronic hypoxia generated by treatment with antiangiogenics. Among other compensatory responses, chronic hypoxia is related with the upregulation of lipidic anabolism. Therefore, we focus on how fatty acid synthase, a key player in this response, can be targeted to delay acquired resistance against antiangiogenics, including experimental data from our group. This effect seems to be specific to those cases in which the antiangiogenic treatment induces a hypoxic response, but not in models where the antiangiogenic agent induced normalizing effects. Whether antiangiogenics induce vascular normalization or a hypoxic environment seems to be tractable with a noninvasive PET-tracer: 18F-fluoromisonidazole PET.