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，Cell Report，2017; Wahl和同事，Cancer Research，2017）表明IDH 1野生型（IDH 1-wt）在2/3的HGG中过表达（在此提及 作为“IDH 1-whigh GBM”），其缺乏IDH 1 R132 H突变。两 单独 而 wt-IDH 1的遗传和药理学抑制， 并与放射治疗（RT）联合减缓患者来源的HGG异种移植物的生长5，6 wt-IDH 1过表达促进颅内HGG生长分子水平，wt-IDH 1高表达 , .关于GBM 产生过量的NADPH，其作为限速还原剂，驱动单- 不饱和脂肪酸（MUFA）。此外，增强的NADPH生产增加谷胱甘肽（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 （GPX 4）驱动的脂质修复，并抑制多不饱和脂肪酸（PUFA）的积累， 过氧化脂质是铁中毒的杀手 基于这些发现，我们假设wt-IDH 1通过增强脂质修复，提高MUFA， 从质膜磷脂中合成和置换可氧化的PUFA拮抗 铁凋亡，一种最近发现的细胞死亡形式，作为一种范式转变迅速获得了认可 专门针对癌细胞的策略。我们进一步假设wt-IDH 1抑制与 已知的铁凋亡诱导剂，包括RT和免疫介导的检查点抑制，以拮抗HGG 进展对于wt-IDH 1的药理学抑制，我们已经使用并表征了13 i，一种首次在 类竞争性β-不饱和烯酮，由AbbVie开发。13 i有效抑制wt-IDH 1酶促 活性，通过共价结合NADP+结合口袋。我们的数据表明13 i促进铁凋亡， 是脑渗透性的，像基因消融一样，减少了IDH 1-wthigh的进展并延长了其生存期。 HGG荷瘤小鼠，单独使用和与RT联合使用。我们将在三个特定目的中检验这些假设： 目的1：确定wt-IDH 1如何影响从头脂肪酸生物合成和膜磷脂 组合物以抑制铁凋亡。 目标二。确定wt-IDH 1如何促进GPX 4依赖性脂质修复和拮抗铁凋亡。 目的3：确定wt-IDH 1的遗传和药理学失活是否会放大小鼠的铁凋亡。 在某些实施方案中，HGG抑制剂能够抑制对RT和免疫检查点阻断的应答并拮抗HGG进展。 目标和长期目标。我们将证明wt-IDH 1作为HGG中铁凋亡的调节剂，并将 使用新型NADP+竞争性抑制剂作为治疗剂验证wt-IDH 1的药理学抑制 战略预计这些研究的结果将为IND使能研究的设计提供信息， 13 i作为抗HGG治疗的佐剂的潜力。