Mouron Silvana, Bueno Maria J, Muñoz Manuel, Quintela-Fandino Miguel
Breast Cancer Clinical Research Unit - Clinical Research Program, CNIO - Spanish National Cancer Research Center, Madrid, Spain.
Medical Oncology, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, Spain.
Oncoscience. 2021 Feb 25;8:1-13. doi: 10.18632/oncoscience.523. eCollection 2021.
Preclinical evidence indicates the potential of targeting mitochondrial respiration as a therapeutic strategy. We previously demonstrated that mitochondrial inhibitors' efficacy was restricted to a metabolic context in which mitochondrial respiration was the predominant energy source, a situation achievable by inducing vascular normalization/hypoxia correction with antiangiogenics. Using molecular imaging, we showed how the same antiangiogenic agent may display different normalizing properties in patients with the same tumor type. This is of key importance, since patients experiencing normalization seem to get more benefit from standard chemotherapy combinations, and also could be eligible for combination with antimitochondrial agents. This scenario emphasizes the need for monitoring vascular normalization in order to optimize the use of antiangiogenics. We have also proposed a method to evaluate anti-mitochondrial agents' pharmacodynamics; despite promising accuracy in animal studies the clinical results were inconclusive, highlighting the need for research in this field. Regarding patients that respond to antiangiogenics increasing vessel abnormality, in this case an immunosuppressive tumor microenvironment is generated. Whether anti-mitochondrial agents can positively modulate the activity of T effector cell subpopulations remains an area of active research. Our research sheds light on the importance of refining the use of antiangiogenics, highlighting the relevance of tracing vascular normalization as a potential biomarker for antiangiogenics to assist patient-tailored medicine and exploring the role of mitochondrial inhibitors in the context of vascular normalization and correction of hypoxia.
临床前证据表明，将线粒体呼吸作为一种治疗策略具有潜力。我们之前证明，线粒体抑制剂的疗效仅限于线粒体呼吸是主要能量来源的代谢环境，这种情况可通过使用抗血管生成药物诱导血管正常化/缺氧纠正来实现。通过分子成像，我们展示了相同的抗血管生成药物在相同肿瘤类型的患者中如何表现出不同的正常化特性。这至关重要，因为经历正常化的患者似乎能从标准化疗联合方案中获得更多益处，并且也可能适合与抗线粒体药物联合使用。这种情况强调了监测血管正常化以优化抗血管生成药物使用的必要性。我们还提出了一种评估抗线粒体药物药效学的方法；尽管在动物研究中准确性令人鼓舞，但临床结果尚无定论，这突出了该领域研究的必要性。对于对抗血管生成药物有反应但血管异常增加的患者，在这种情况下会产生免疫抑制性肿瘤微环境。抗线粒体药物是否能正向调节T效应细胞亚群的活性仍是一个活跃的研究领域。我们的研究揭示了优化抗血管生成药物使用的重要性，强调了追踪血管正常化作为抗血管生成药物潜在生物标志物以辅助个体化医疗的相关性，并探索了线粒体抑制剂在血管正常化和缺氧纠正背景下的作用。
