Department of Dermatology, Duke University Medical Center, Durham, North Carolina.
Department of Pathology, Duke University Medical Center, Durham, North Carolina.
Cancer Res. 2024 Nov 4;84(21):3640-3656. doi: 10.1158/0008-5472.CAN-24-0134.
Radiotherapy (RT) is commonly used to try to eliminate any remaining tumor cells following surgical resection of glioma. However, tumor recurrence is prevalent, highlighting the unmet medical need to develop therapeutic strategies to enhance the efficacy of RT in glioma. Focusing on the radiosensitizing potential of the currently approved drugs known to cross the blood-brain barrier can facilitate rapid clinical translation. Here, we assessed the role of catechol-O-methyltransferase (COMT), a key enzyme to degrade catecholamines and a drug target for Parkinson's disease, in glioma treatment. Analysis of The Cancer Genome Atlas data showed significantly higher COMT expression levels in both low-grade glioma and glioblastoma compared to normal brain tissues. Inhibition of COMT by genetic knockout or FDA-approved COMT inhibitors significantly sensitized glioma cells to RT in vitro and in vivo. Mechanistically, COMT inhibition in glioma cells led to mitochondria dysfunction and increased mitochondrial RNA release into the cytoplasm, activating the cellular antiviral double-stranded RNA sensing pathway and type I interferon (IFN) response. Elevated type I IFNs stimulated the phagocytic capacity of microglial cells, enhancing RT efficacy. Given the long-established safety record of the COMT inhibitors, these findings provide a solid rationale to evaluate them in combination with RT in patients with glioma. Significance: Inhibition of catechol-O-methyltransferase, a well-established drug target in Parkinson's disease, interferes with mitochondrial electron transport and induces mitochondrial double-stranded RNA leakage, activating type I interferon signaling and sensitizing glioma to radiotherapy.
放射治疗（RT）通常用于尝试消除神经胶质瘤手术后任何残留的肿瘤细胞。然而，肿瘤复发很常见，这突显了开发治疗策略以增强 RT 在神经胶质瘤中的疗效的未满足的医疗需求。关注目前已批准的可穿透血脑屏障的药物的放射增敏潜力，可以促进快速的临床转化。在这里，我们评估了儿茶酚-O-甲基转移酶（COMT）在神经胶质瘤治疗中的作用，COMT 是一种降解儿茶酚胺的关键酶，也是帕金森病的药物靶点。对癌症基因组图谱数据的分析表明，低级别神经胶质瘤和胶质母细胞瘤中的 COMT 表达水平明显高于正常脑组织。通过基因敲除或 FDA 批准的 COMT 抑制剂抑制 COMT，可显著增强神经胶质瘤细胞对体外和体内 RT 的敏感性。从机制上讲，神经胶质瘤细胞中 COMT 的抑制导致线粒体功能障碍和线粒体 RNA 向细胞质释放增加，激活细胞抗病毒双链 RNA 感应途径和 I 型干扰素（IFN）反应。I 型 IFN 的升高刺激小胶质细胞的吞噬能力，增强 RT 的疗效。鉴于 COMT 抑制剂的长期安全性记录，这些发现为评估它们与 RT 联合治疗神经胶质瘤患者提供了坚实的理由。意义：抑制儿茶酚-O-甲基转移酶，一种在帕金森病中确立的药物靶点，干扰线粒体电子传递并诱导线粒体双链 RNA 泄漏，激活 I 型干扰素信号转导并使神经胶质瘤对放射治疗敏感。
