Inhibition of wild-type IDH1 as a ferroptosis-inducing therapeutic approach for the treatment of malignant glioma.

抑制野生型 IDH1 作为治疗恶性神经胶质瘤的铁死亡诱导治疗方法。

• 批准号: 10539153
• 负责人: Alexander H. Stegh
• 金额: $ 49.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539153
• 关键词: Ablation; Adjuvant; Anabolism; Binding; Brain; Cell Death; Cell membrane; Cells; Data; Enzymes; Genetic; Glioma; Glutathione; Goals; Growth; Immune; Isocitrate Dehydrogenase; Laboratories; Lipid Peroxides; Lipids; Malignant Glioma; Mediating; Membrane; Metabolic; Molecular; Monounsaturated Fatty Acids; Mus; Mutation; NADP; Patients; Pharmacology; Phospholipids; Polyunsaturated Fatty Acids; Production; Radiation therapy; Reactive Oxygen Species; Reducing Agents; Reporting; Role; Testing; Therapeutic; Xenograft procedure; anticancer research; base; cancer cell; checkpoint inhibition; design; fatty acid biosynthesis; glutathione peroxidase; immune checkpoint blockade; inhibitor; novel; novel therapeutic intervention; overexpression; radiation response; repaired

Our laboratories recent studies (Stegh and colleagues, Cell Report, 2017; Wahl and colleagues, Cancer Research, 2017) indicated that IDH1 wild-type (IDH1-wt) is overexpressed in 2/3 of HGG (referred to here as `IDH1-wthigh GBM') that lack IDH1R132H mutation. Both alone while genetic and pharmacological inhibition of wt-IDH1, and in combination with radiation therapy (RT) slows the growth of patient-derived HGG xenografts 5,6 overexpression of wt-IDH1 promotes intracranial HGG growth molecular levels, wt-IDH1 high , . On GBM produce excess NADPH, which serves as a rate-limiting reductant that drives the biosynthesis of mono- unsaturated fatty acids (MUFAs). In addition, enhanced NADPH production increases glutathione (GSH) level, reduces reactive oxygen species (ROS), activates phospholipidperoxidase glutathione peroxidase 4 (GPX4)-drivenlipid repair, and dampensthe accumulation of polyunsaturated fatty acid (PUFA)-containing lipid peroxides, known executioners of ferroptosis. Based on these findings, we hypothesize that wt-IDH1 through enhanced lipid repair, heightened MUFA biosynthesis and displacement of oxidizable PUFAs from plasma membrane phospholipids antagonizes ferroptosis, a recently discovered form of cell death has rapidly gained recognition as a paradigm shifting strategy to specifically target cancer cells. We further hypothesize that wt-IDH1 inhibition cooperates with known inducers of ferroptosis, including RT and immune-mediated checkpoint inhibition, to antagonize HGG progression. For the pharmacological inhibition of wt-IDH1, we have used and characterized 13i, a first-in- class competitive -unsaturated enone, developed by AbbVie. 13i potently inhibits wt-IDH1 enzymatic activity, by covalently binding to the NADP+ binding pocket. Our data indicate that 13i promotes ferroptosis, is brain-penetrant, and like genetic ablation, reduces progression and extends the survival of IDH1-wthigh HGG bearing mice, alone and in combination with RT. We will test these hypotheses in three Specific Aims: Aim 1: Determine how wt-IDH1 impacts de novo fatty acid biosynthesis and membrane phospholipid composition to inhibit ferroptosis. Aim 2. Determine how wt-IDH1 promotes GPX4-dependent lipid repair and antagonizes ferroptosis. Aim 3: Determine if genetic and pharmacological inactivation of wt-IDH1 amplifies ferroptosis in response to RT and immune checkpoint blockade and antagonizes HGG progression. Objectives and long-term goals. We will credential wt-IDH1 as regulator of ferroptosis in HGG and will validate the pharmacological inhibition of wt-IDH1 using a novel NADP+ competitive inhibitor as a therapeutic strategy. Results from these studies are expected to inform the design of IND-enabling studies evaluating the potential of 13i as adjuvant for anti-HGG therapy.

我们的实验室最近的研究（Stegh 和同事，细胞报告，2017 年；Wahl 和同事，癌症 Research, 2017) 表明 IDH1 野生型 (IDH1-wt) 在 2/3 的 HGG 中过表达（参考此处 缺乏 IDH1R132H 突变的“IDH1-wthigh GBM”。 独自的 尽管 wt-IDH1 的遗传和药理学抑制， 与放射治疗 (RT) 相结合可减缓患者来源的 HGG 异种移植物的生长 5,6 wt-IDH1过表达促进颅内HGG生长分子水平，wt-IDH1高 , .关于GBM 产生过量的 NADPH，它作为限速还原剂，驱动单-生物合成 此外，NADPH 产量的增加会增加谷胱甘肽 (GSH)。 水平，减少活性氧 (ROS)，激活磷脂过氧化物酶谷胱甘肽过氧化物酶 4 (GPX4) 驱动的脂质修复，并抑制含多不饱和脂肪酸 (PUFA) 的积累 脂质过氧化物，已知的铁死亡刽子手。 基于这些发现，我们通过增强脂质修复、富有成效的 MUFA 来追求 wt-IDH1 质膜磷脂中可氧化多不饱和脂肪酸的生物合成和置换会拮抗 铁死亡是一种最近发现的细胞死亡形式，作为一种范式转变迅速得到认可 我们进一步研究了 wt-IDH1 抑制与癌细胞的协同作用。 已知的铁死亡诱导剂，包括 RT 和免疫介导的检查点抑制，以拮抗 HGG 对于 wt-IDH1 的药理学抑制，我们使用并表征了 13i，这是一种首创的 由 AbbVie 开发的同类竞争性 α-不饱和烯酮，可有效抑制 wt-IDH1 酶。 通过与 NADP+ 结合袋共价结合，我们的数据表明 13i 促进铁死亡， 具有脑渗透性，与基因消融一样，可减少 IDH1-wthigh 的进展并延长其生存期 携带 HGG 的小鼠，单独使用或与 RT 结合使用，我们将在三个具体目标中测试这些假设： 目标 1：确定 wt-IDH1 如何影响从头脂肪酸生物合成和膜磷脂 抑制铁死亡的组合物。 目标 2. 确定 wt-IDH1 如何促进 GPX4 依赖性脂质修复并拮抗铁死亡。 目标 3：确定 wt-IDH1 的遗传和药理学失活是否会放大铁死亡 对 RT 和免疫检查点阻断的反应并拮抗 HGG 进展。 目标和长期目标 我们将证明 wt-IDH1 作为 HGG 中铁死亡的调节剂。 使用新型 NADP+ 竞争性抑制剂作为治疗方法验证 wt-IDH1 的药理学抑制作用 这些研究的结果预计将为评估 IND 的研究设计提供信息。 13i 作为抗 HGG 治疗佐剂的潜力。