Targeting Defective DNA Damage Response Pathways in IDH1/2-mutant AML

针对 IDH1/2 突变 AML 中的缺陷 DNA 损伤反应途径

• 批准号: 10345137
• 负责人: Ranjit Bindra
• 金额: $ 58.51万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-03 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10345137
• 关键词: Acute Myelocytic Leukemia; Binding; Cessation of life; Citric Acid Cycle; Clinic; Clinical Trials; Collection; Combined Modality Therapy; Cytostatics; DNA; DNA Damage; DNA Double Strand Break; DNA Repair Pathway; Data; Defect; Dioxygenases; Double Strand Break Repair; Engineering; Enzymes; Epigenetic Process; Event; FDA approved; Gene Mutation; Genes; Histones; Hypermethylation; Impairment; In Vitro; In complete remission; Induced Mutation; Isocitrate Dehydrogenase; Isocitrates; Lead; Long-Term Survivors; Lysine; Malignant Neoplasms; Masks; Metabolic; Mitogen-Activated Protein Kinases; Modeling; Mus; Mutation; Newly Diagnosed; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Poly(ADP-ribose) Polymerases; Production; Protein Isoforms; Relapse; Reporting; Resistance; SRSF2 gene; Signal Pathway; Signal Transduction; Site; Specimen; Supportive care; Testing; Therapeutic; Toxic effect; Translating; Treatment Efficacy; Tricarboxylic Acids; Work; Xenograft procedure; alpha ketoglutarate; base; chemotherapy; cytokine; efficacy testing; enzyme activity; hematopoietic differentiation; homologous recombination; in vivo; in vivo Model; inhibitor; insight; leukemia; leukemogenesis; molecular subtypes; mutant; novel therapeutic intervention; resistance mechanism; response; restoration; targeted treatment; therapeutic target; therapy resistant; tumor

Heterozygous mutations in two key metabolic genes, isocitrate dehydrogenase-1 and -2 (IDH1/2), are present in up to 20% of newly diagnosed AML patients. IDH1/2 enzymes convert isocitrate to a-ketoglutarate (aKG) in the tricarboxylic acid (TCA) cycle. IDH1/2 mutations impart a neomorphic enzyme activity, leading to the conversion of aKG to the oncometabolite, 2-hydroxyglutarate (2HG). 2HG competitively inhibits aKG- dependent dioxygenases, which induces profound epigenetic alterations and impaired hematopoietic differentiation. IDH1/2 inhibitors are now FDA-approved for AML, although these agents typically are not curative, with complete response (CR) rates and median overall survival (OS) ranging between 20-30% and ~8-12 months, respectively. In addition, primary and acquired resistance to mutant IDH1/2 inhibitors commonly occurs. The inability to achieve a cure with these drugs as a monotherapy in part can be attributed to their mechanism of action. Specifically, these drugs act in a cytostatic manner via the induction of differentiation, which is highlighted by persistence of mutant IDH1/2 clones in the majority of patients, even those who achieve a CR. These data underscore the need to develop alternative approaches to target IDH1/2-mutant AML. Our team recently discovered that IDH1/2 mutations induce a DNA damage response (DDR) defect which confers sensitivity to poly(ADP)-ribose polymerase (PARP) inhibitors. Mechanistically, we demonstrated that 2HG-induced inhibition of the lysine demethylase, KDM4B, results in aberrant hypermethylation of histone 3 lysine 9 (H3K9) at loci surrounding DNA breaks, masking a local H3K9 trimethylation signal that is essential for the proper execution of homologous recombination (HR), a key DNA double-strand break (DSB) repair pathway. We also extended these findings to other TCA gene mutations which create oncometabolites, which we have collectively termed “oncometabolite-induced BRCAness”. Our work suggests that oncometabolite- induced BRCAness is tumor type-agnostic, and we are now directly translating this work into multiple clinical trials, which currently are testing the efficacy of PARP inhibitors against IDH1/2-mutant cancers, including AML (NCT03953898; the PRIME trial; PI: Prebet). It is now well-established that IDH1/2 mutations induce DDR defects in AML, and here we propose to study: (a) the impact of common, co-occurring mutations in AML on the associated DDR defect, which will be critical for therapeutic targeting; (b) which DDR inhibitors will be most effective, and whether combinations with other systemic agents in AML will increase efficacy; and (c) the extent to which our DDR inhibitor-based strategies will be effective against tumors with intrinsic or acquired resistance to therapy. These studies have the potential to establish an entirely new therapeutic approach for newly diagnosed and relapsed IDH1/2- mutant AML, which exploits DDR defects identified by our team. By focusing on drugs which are either FDA- approved or in clinical trials, our work can be rapidly translated into the clinic.

两个关键代谢基因异柠檬酸脱氢酶-1和-2（IDH 1/2）的杂合突变， 存在于高达20%的新诊断的AML患者中。IDH 1/2酶将异柠檬酸转化为α-酮戊二酸 (aKG)三羧酸（TCA）循环。IDH 1/2突变赋予新变体酶活性，导致 aKG转化为癌代谢物2-羟基戊二酸（2 HG）。2 HG竞争性抑制aKG- 依赖性双加氧酶，其诱导深刻的表观遗传改变和受损的造血 分化IDH 1/2抑制剂现在被FDA批准用于AML，尽管这些药物通常不是 治愈性，完全缓解率（CR）和中位总生存期（OS）范围为20-30%， ~8-12个月，分别。此外，对突变型IDH 1/2抑制剂的原发性和获得性抗性通常 发生。这些药物作为单一疗法无法治愈的部分原因可能是它们 作用机制。具体地，这些药物通过诱导分化以细胞抑制方式起作用， 这突出表现在大多数患者中突变IDH 1/2克隆的持续存在，即使是那些实现了IDH 1/2克隆的患者， 一个CR。这些数据强调了开发靶向IDH 1/2突变型AML的替代方法的必要性。 我们的团队最近发现IDH 1/2突变诱导DNA损伤反应（DDR）缺陷， 赋予对聚（ADP）-核糖聚合酶（PARP）抑制剂的敏感性。从机制上讲，我们证明， 2 HG诱导的赖氨酸脱甲基酶KDM 4 B抑制导致组蛋白3异常高甲基化 赖氨酸9（H3 K9）在基因座周围的DNA断裂，掩盖了局部H3 K9三甲基化信号，这是必要的， 正确执行同源重组（HR），这是一种关键的DNA双链断裂（DSB）修复 通路我们还将这些发现扩展到其他导致肿瘤的TCA基因突变， 我们统称为“肿瘤代谢产物诱导的BRCAness”。我们的研究表明肿瘤代谢物- 诱导的BRCAness是肿瘤类型不可知的，我们现在正直接将这项工作转化为多个临床 目前正在测试PARP抑制剂对IDH 1/2突变型癌症（包括AML）的疗效 （NCT 03953898; PRIME试验; PI：Prebet）。 现在已经确定IDH 1/2突变在AML中诱导DDR缺陷，在此我们建议 研究：（a）AML中常见的共同发生的突变对相关DDR缺陷的影响， （B）哪些DDR抑制剂将是最有效的，以及是否与 其他系统性药物治疗AML将提高疗效;以及（c）我们的DDR治疗方案在多大程度上 这些策略将有效对抗对治疗具有内在或获得性抗性的肿瘤。这些研究 为新诊断和复发的IDH 1/2建立一种全新治疗方法的潜力- 突变AML，它利用了我们团队发现的DDR缺陷。把重点放在食品药品监督管理局- 无论是获批还是临床试验，我们的工作都可以迅速转化为临床应用。