小柯机器人

美国德州大学西南医学中心Samuel K. McBrayer和美国哈佛医学院William G. Kaelin Jr.团队共同合作，近期取得重要工作进展。他们研究发现嘧啶从头合成途径可以作为IDH突变型神经胶质瘤的治疗靶点。这一研究成果2022年8月18日在线发表于《癌细胞》杂志上。

通过化学合成致死筛选，研究人员发现IDH1突变的胶质瘤细胞对靶向嘧啶核苷酸从头合成途径相关酶的药物比较敏感，包括二氢乳清酸脱氢酶（DHODH）。研究人员开发了IDH1突变体驱动的星形细胞瘤的基因工程小鼠模型，并使用它和多个患者来源的模型来证明脑渗透性DHODH抑制剂BAY 2402234对IDH突变型神经胶质瘤具有单药疗效。从机制上讲，这反映了神经胶质瘤细胞对嘧啶从头合成途径的固有依赖性，以及突变型IDH在核苷酸池失衡时对DNA损伤敏感的能力。他们的工作概述了一种肿瘤选择性、生物标志物指导的治疗策略，该策略有望用于临床转化。

据介绍，影响异柠檬酸脱氢酶(IDH)的突变在胶质瘤、白血病和其他癌症中普遍存在。虽然突变型IDH抑制剂对白血病有效，但它们在恶性胶质瘤中的活性比较低，这强调了替代治疗策略的必要性。

附：英文原文

Title: De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma

Author: Diana D. Shi, Milan R. Savani, Michael M. Levitt, Adam C. Wang, Jennifer E. Endress, Cylaina E. Bird, Joseph Buehler, Sylwia A. Stopka, Michael S. Regan, Yu-Fen Lin, Vinesh T. Puliyappadamba, Wenhua Gao, Januka Khanal, Laura Evans, Joyce H. Lee, Lei Guo, Yi Xiao, Min Xu, Bofu Huang, Rebecca B. Jennings, Dennis M. Bonal, Misty S. Martin-Sandoval, Tammie Dang, Lauren C. Gattie, Amy B. Cameron, Sungwoo Lee, John M. Asara, Harley I. Kornblum, Tak W. Mak, Ryan E. Looper, Quang-De Nguyen, Sabina Signoretti, Stefan Gradl, Andreas Sutter, Michael Jeffers, Andreas Janzer, Mark A. Lehrman, Lauren G. Zacharias, Thomas P. Mathews, Julie-Aurore Losman, Timothy E. Richardson, Daniel P. Cahill, Ralph J. DeBerardinis, Keith L. Ligon, Lin Xu, Peter Ly, Nathalie Y.R. Agar, Kalil G. Abdullah, Isaac S. Harris, William G. Kaelin, Samuel K. McBrayer

Issue&Volume: 2022-08-18

Abstract: Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they seem to be less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1-mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH-mutant gliomas. Mechanistically, this reflects an obligate dependence of glioma cells on the de novo pyrimidine synthesis pathway and mutant IDH’s ability to sensitize to DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.

DOI: 10.1016/j.ccell.2022.07.011

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00324-5

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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