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.

两个关键代谢基因的杂合突变，异位酸脱氢酶1和-2（IDH1/2）是 最多有20％的新诊断为AML患者。 IDH1/2酶将异位酸转化为A-Ketoglutarate （AKG）在三核酸（TCA）周期中。 IDH1/2突变赋予新态酶活性，导致 AKG转换为oncometabolite，2-羟基戊二酸（2HG）。 2HG竞争性抑制AKG- 依赖性双氧酶，诱导深刻的表观遗传改变和造血性障碍 分化。现在，IDH1/2抑制剂已被FDA批准用于AML，尽管这些试剂通常不是 治愈性，完全响应（CR）率和中位总生存期（OS）在20-30％之间 分别〜8-12个月。另外，通常对突变体IDH1/2抑制剂的抗性通常 发生。无法将这些药物作为单一疗法的治愈方法部分归因于他们 作用机理。具体而言，这些药物通过诱导分化，以细胞抑制作用作用， 突变体IDH1/2克隆在大多数患者中，即使是那些实现的患者都可以突出显示 Cr。这些数据强调了开发针对IDH1/2突变AML的替代方法的必要性。 我们的团队最近发现IDH1/2突变会引起DNA损伤响应（DDR）缺陷 赋予对聚（ADP） - 脱伯糖聚合酶（PARP）抑制剂的敏感性。从机械上讲，我们证明了 2HG诱导的赖氨酸脱甲基酶KDM4B的抑制导致组蛋白3的异常高甲基化3 赖氨酸9（H3K9）在周围DNA断裂的局部裂纹，掩盖了局部H3K9三甲基化信号，这对于对 同源重组（HR）的正确执行，键DNA双链（DSB）修复 路径。我们还将这些发现扩展到其他TCA基因突变，这些突变产生了oncometabolites， 我们集体称为“ oncometabolite引起的BRCANESS”。我们的工作表明oncometabolite- 诱导的BRCANESS是肿瘤型敏锐的，我们现在直接将这项工作转化为多个临床 试验，目前正在测试PARP抑制剂对IDH1/2突变癌的效率，包括AML （NCT03953898； Prime试验； PI：Prebet）。 现在，IDH1/2突变诱导AML中的DDR缺陷已经良好，在这里我们建议 研究：（a）AML中常见的，共同发生的突变对相关DDR缺陷的影响，这将是 对于治疗靶向至关重要； （b）哪种DDR抑制剂将最有效，以及与 AML中的其他系统性代理将提高效率； （c）我们的DDR抑制剂在多大程度上 策略将有效抵抗具有固有或获得耐药性的肿瘤。这些研究有 建立一种全新的治疗方法的潜力，用于新诊断和中继IDH1/2-- 突变AML，利用我们团队确定的DDR缺陷。通过专注于FDA-的药物 批准或在临床试验中，我们的工作可以迅速转化为诊所。