Department of Radiation Oncology, Wexner Medical Center and Comprehensive Cancer Center The Ohio State University Columbus, OH, USA.
Br J Radiol. 2020 Nov 1;93(1115):20200067. doi: 10.1259/bjr.20200067. Epub 2020 Jun 23.
Cancer-specific metabolic changes support the anabolic needs of the rapidly growing tumor, maintain a favorable redox balance, and help cells adapt to microenvironmental stresses like hypoxia and nutrient deprivation. Radiation is extensively applied in a large number of cancer treatment protocols but despite its curative potential, radiation resistance and treatment failures pose a serious problem. Metabolic control of DNA integrity and genomic stability can occur through multiple processes, encompassing cell cycle regulation, nucleotide synthesis, epigenetic regulation of gene activity, and antioxidant defenses. Given the important role of metabolic pathways in oxidative damage responses, it is necessary to assess the potential for tumor-specific radiosensitization by novel metabolism-targeted therapies. Additionally, there are opportunities to identify molecular and functional biomarkers of vulnerabilities to combination treatments, which could then inform clinical decisions. Here, we present a curated list of metabolic pathways in the context of ionizing radiation responses. Glutamine metabolism influences DNA damage responses by mechanisms such as synthesis of nucleotides for DNA repair or of glutathione for ROS detoxification. Repurposed oxygen consumption inhibitors have shown promising radiosensitizing activity against murine model tumors and are now in clinical trials. Production of 2-hydroxy glutarate by isocitrate dehydrogenase1/2 neomorphic oncogenic mutants interferes with the function of α-ketoglutarate-dependent enzymes and modulates Ataxia Telangiectasia Mutated (ATM) signaling and glutathione pools. Radiation-induced oxidative damage to membrane phospholipids promotes ferroptotic cell loss and cooperates with immunotherapies to improve tumor control. In summary, there are opportunities to enhance the efficacy of radiotherapy by exploiting cell-inherent vulnerabilities and dynamic microenvironmental components of the tumor.
癌症特异性代谢变化支持快速生长的肿瘤的合成代谢需求，维持有利的氧化还原平衡，并帮助细胞适应缺氧和营养剥夺等微环境应激。辐射被广泛应用于大量癌症治疗方案中，但尽管有治愈潜力，辐射抗性和治疗失败仍是一个严重的问题。DNA 完整性和基因组稳定性的代谢控制可以通过多种过程发生，包括细胞周期调节、核苷酸合成、基因活性的表观遗传调节和抗氧化防御。鉴于代谢途径在氧化损伤反应中的重要作用，有必要通过新的代谢靶向治疗来评估肿瘤特异性放射增敏的潜力。此外，还有机会确定对联合治疗的脆弱性的分子和功能生物标志物，然后为临床决策提供信息。在这里，我们在电离辐射反应的背景下呈现了一个经过精心挑选的代谢途径列表。谷氨酰胺代谢通过为 DNA 修复合成核苷酸或为 ROS 解毒合成谷胱甘肽等机制影响 DNA 损伤反应。重新利用的氧消耗抑制剂已显示出对鼠模型肿瘤有有前途的放射增敏活性，目前正在临床试验中。异柠檬酸脱氢酶 1/2 新形癌基因突变体产生的 2-羟基戊二酸会干扰α-酮戊二酸依赖性酶的功能，并调节共济失调毛细血管扩张突变（ATM）信号和谷胱甘肽池。辐射诱导的膜磷脂氧化损伤促进铁死亡细胞丢失，并与免疫疗法合作改善肿瘤控制。总之，通过利用细胞固有脆弱性和肿瘤动态微环境成分，有机会提高放射治疗的疗效。
