密歇根大学Sriram Venneti研究团队揭示了异柠檬酸脱氢酶1启动组-3髓母细胞瘤治疗铜增生。相关论文于2025年5月15日发表于国际顶尖学术期刊《癌细胞》杂志上。

为了确定可操作的代谢依赖性，该课题组人员在预后不良的3MB组中发现了丙酮酸脱氢酶复合物（PDC）E2亚基二氢脂酰基转乙酰化酶（DLAT）的上调。DLAT由c-MYC诱导，靶向DLAT可降低TCA循环代谢和谷胱甘肽合成。研究人员还注意到，异柠檬酸脱氢酶1 （IDH1）基因表达在3组MB患者肿瘤中上调，IDH1的抑制在多种c-MYC扩增的癌症中表观遗传地降低了c-MYC和下游DLAT水平。DLAT是铜离子载体埃司氯莫尔诱导的铜细胞凋亡（铜依赖性细胞死亡）的中心调节剂。3组MB细胞中DLAT的表达与铜增生敏感性增加相关。在多种组- 3MB动物模型中，Elesclomol具有脑渗透和抑制肿瘤生长的作用。他们的数据揭示了IDH1/c-MYC依赖性漏洞，该漏洞调节DLAT水平，并且可以通过铜变杀死组- 3MB。

据介绍，MYC驱动的3组髓母细胞瘤（MBs）是无法治愈的儿童恶性脑癌。

附：英文原文

Title: Isocitrate dehydrogenase 1 primes group-3 medulloblastomas for cuproptosis

Author: Derek Dang, Akash Deogharkar, John McKolay, Kyle S. Smith, Pooja Panwalkar, Simon Hoffman, Wentao Tian, Sunjong Ji, Ana P. Azambuja, Siva Kumar Natarajan, Joanna Lum, Jill Bayliss, Katie Manzeck, Stefan R. Sweha, Erin Hamanishi, Matthew Pun, Diya Patel, Sagar Rau, Olamide Animasahun, Abhinav Achreja, Martin P. Ogrodzinski, Jutta Diessl, Jennifer Cotter, Debra Hawes, Fusheng Yang, Robert Doherty, Andrea T. Franson, Allison R. Hanaford, Charles G. Eberhart, Eric H. Raabe, Brent A. Orr, Robert J. Wechsler-Reya, Brandon Chen, Costas A. Lyssiotis, Yatrik M. Shah, Sophia Y. Lunt, Ruma Banerjee, Alexander R. Judkins, John R. Prensner, Carl Koschmann, Sebastian M. Waszak, Deepak Nagrath, Marcos Simoes-Costa, Paul A. Northcott, Sriram Venneti

Issue&Volume: 2025-05-15

Abstract: MYC-driven group-3 medulloblastomas (MBs) are malignant pediatric brain cancers without cures. To define actionable metabolic dependencies, we identify upregulation of dihydrolipoyl transacetylase (DLAT), the E2-subunit of pyruvate dehydrogenase complex (PDC) in a subset of group-3 MB with poor prognosis. DLAT is induced by c-MYC and targeting DLAT lowers TCA cycle metabolism and glutathione synthesis. We also note upregulation of isocitrate dehydrogenase 1 (IDH1) gene expression in group-3 MB patient tumors and suppression of IDH1 epigenetically reduces c-MYC and downstream DLAT levels in multiple c-MYC amplified cancers. DLAT is a central regulator of cuproptosis (copper-dependent cell death) induced by the copper ionophore elesclomol. DLAT expression in group-3 MB cells correlates with increased sensitivity to cuproptosis. Elesclomol is brain-penetrant and suppresses tumor growth in vivo in multiple group-3 MB animal models. Our data uncover an IDH1/c-MYC dependent vulnerability that regulates DLAT levels and can be targeted to kill group-3 MB by cuproptosis.

DOI: 10.1016/j.ccell.2025.04.013

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00172-2