Antiangiogenic Resistance and Cancer Metabolism: Opportunities for Synthetic Lethality
Autor: | Simon Lord, Miguel Quintela-Fandino, Adrian L. Harris, Juan M. Funes |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Cell Survival Angiogenesis Clinical Biochemistry Angiogenesis Inhibitors Synthetic lethality Biology Pharmacology 03 medical and health sciences 0302 clinical medicine Neoplasms Drug Discovery medicine Animals Humans Gene Regulatory Networks Precision Medicine Cell Proliferation Glutaminolysis Cancer medicine.disease Metabolic pathway 030104 developmental biology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Molecular Medicine Lethality Signal transduction Synthetic Lethal Mutations Metabolic Networks and Pathways Signal Transduction |
Zdroj: | Current Drug Targets. 17:1714-1727 |
ISSN: | 1389-4501 |
Popis: | 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. |
Databáze: | OpenAIRE |
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