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Antiangiogenics and Hypoxic Response: Role of Fatty Acid Synthase Inhibitors
Maria Jose Bueno, Jesus Sanchez, Ramon Colomer
1Breast Cancer Clinical Research Unit, CNIO - Spanish National Cancer Research Center, Melchor Fernandez Almagro, 3, Madrid, 28029, Spain.
Abstract:
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.
Insights
Antiangiogenic drugs may work by vascular choking, causing hypoxia and resistance. Targeting fatty acid synthase can overcome this resistance, particularly when hypoxia is induced, which can be monitored using 18F-fluoromisonidazole PET scans.
Area of Science:
- Oncology
- Vascular Biology
- Pharmacology
Background:
- Antiangiogenic therapies in epithelial malignancies aim to normalize tumor vasculature, improving drug delivery and oxygenation.
- Resistance to antiangiogenics is a significant clinical challenge, with various proposed mechanisms.
- Vascular choking, leading to increased tumor hypoxia, is an under-explored mechanism of antiangiogenic action.
Purpose of the Study:
- To review evidence for vascular choking as an antiangiogenic mechanism of action.
- To explore resistance mechanisms to antiangiogenic-induced hypoxia.
- To investigate targeting fatty acid synthase to overcome antiangiogenic resistance.
Main Methods:
- Review of preclinical and clinical evidence on antiangiogenic-induced decreased blood flow.
- Analysis of compensatory responses to chronic hypoxia, including lipidic anabolism.
- Evaluation of fatty acid synthase inhibition in models of antiangiogenic resistance.
- Utilizing 18F-fluoromisonidazole PET to differentiate vascular normalization from hypoxia.
Main Results:
- Antiangiogenics can induce vascular choking and hypoxia, distinct from vascular normalization.
- Chronic hypoxia promotes lipidic anabolism, with fatty acid synthase as a key mediator.
- Targeting fatty acid synthase can delay acquired resistance to antiangiogenics that induce hypoxia.
- The effect of targeting fatty acid synthase is specific to hypoxic antiangiogenic responses, not normalizing ones.
- 18F-fluoromisonidazole PET can distinguish between antiangiogenic-induced vascular normalization and hypoxia.
Conclusions:
- Vascular choking is a relevant antiangiogenic mechanism, leading to hypoxia and potential resistance.
- Inhibition of fatty acid synthase offers a strategy to overcome resistance in hypoxic antiangiogenic therapy.
- Noninvasive PET imaging can guide the selection of antiangiogenic strategies based on their effect on tumor oxygenation.
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