摘要
抗血管新生阻力是癌症治疗中一个主要的难题:临床前研究已经确定了几种能够抑制血管内皮抑制因子的代偿性血管通路,其中几个通路已经促进了新药的发展。然而,在血管再生系统中两个或两个以上的靶向制剂的联合使用会受到毒性的限制,因为这个系统关联着正常生理状态。本文提出了一个提高药物级别有效性的方法,该方法利用了肿瘤代谢异常的优势。癌症代谢不同于正常细胞的特点在于:糖酵解、谷氨酰胺、戊糖磷酸分流以及三羧酸循环补缺的转变的增加。此外,这种偏差多由药物靶向引起的常见变化引起。抗血管增生可能会通过影响养料和氧气供给来阻碍癌症维持代谢异常,也正因为此可能会诱导一些代谢通路成为肿瘤存活的必需条件(诱导性和致命性,一种合成致死)。因此,那些非必需的代谢信号通路当抗血管增生受到抑制时可能会诱导合成致死。然而这个关键的问题是介于病人间以及肿瘤内异质性,因为不是所有患有同类型肿瘤的病人在抗血管增生方面表达一致的代谢特征和代谢重整。每一种癌症都有异构缺氧区。整合代谢的动态踪迹可能会使我们利用条件窗设计的优势来调整我们对与抗血管增生联合使用药物的选择。
关键词: 抗血管新生;癌症代谢;组织缺氧;代谢重整;线粒体开关;合成致死
图形摘要
Current Drug Targets
Title:Antiangiogenic Resistance and Cancer Metabolism: Opportunities for Synthetic Lethality
Volume: 17 Issue: 15
Author(s): Simon Lord, Juan M. Funes, Adrian L Harris, Miguel Quintela-Fandino
Affiliation:
关键词: 抗血管新生;癌症代谢;组织缺氧;代谢重整;线粒体开关;合成致死
摘要: Antiangiogenic resistance is a major problem in cancer therapeutics. Preclinical research has identified several compensatory proangiogenic pathways that arise upon vascular endothelial growth factor inhibition, several of which have led to the development of novel drugs. However, the combination of two or more targeted agents in the angiogenesis system is hampered by toxicity, as the system is involved in normal physiology. We propose a different approach for improving the efficacy of this drug class, which takes advantage of aberrant cancer metabolism. Several features distinguish cancer metabolism from that of normal cells, including increased glycolysis, glutaminolysis, and pentose-phosphate shunt, as well as an anaplerotic shift of the Krebs cycle. In addition, these aberrations are driven by most of the common mutations that can be targeted by drugs. Antiangiogenics may hamper the ability of cancer to sustain aberrant metabolism due to their impacts on nutrient and oxygen supplies, and thus they may induce some metabolic pathways to become essential for tumor survival (induced essentiality or contextual lethality, a type of synthetic lethality). Thus, some metabolic and signaling pathways that are otherwise nonessential may induce synthetic lethality when inhibited in combination with antiangiogenics. The key problems, however, are interpatient and intratumor heterogeneity, as not all patients with the same tumor type show the same metabolic traits and the same metabolic reprogramming in response to antiangiogenics. With each cancer there are heterogeneous hypoxic areas. Integrating dynamic tracking of metabolism may allow us to tailor our choices of companion drugs with antiangiogenics, taking advantage of window-of-opportunity designs.
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Cite this article as:
Simon Lord, Juan M. Funes, Adrian L Harris, Miguel Quintela-Fandino , Antiangiogenic Resistance and Cancer Metabolism: Opportunities for Synthetic Lethality, Current Drug Targets 2016; 17 (15) . https://dx.doi.org/10.2174/1389450117666160307143718
DOI https://dx.doi.org/10.2174/1389450117666160307143718 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
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