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

基本信息

批准号：
10561637
负责人：
Ranjit Bindra
金额：
$ 57.34万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10561637
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 DNMT3a Data Defect Dioxygenases Double Strand Break Repair Engineering Enzymes Epigenetic Process Event FDA approved FLT3 gene Gene Mutation Genes Heterozygote Histones Hypermethylation Immunologic Deficiency Syndromes Impairment In Vitro In complete remission Induced Mutation Isocitrate Dehydrogenase Isocitrates Long-Term Survivors Lysine Malignant Neoplasms Metabolic Methylation Mitogen-Activated Protein Kinases Modeling Mus Mutation Newly Diagnosed Pathway interactions Patients Pharmaceutical Preparations Phenotype Poly(ADP-ribose) Polymerase Inhibitor 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 Model alpha ketoglutarate chemotherapy cytokine drug action 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 synthetic lethal interaction targeted treatment therapeutic target therapy resistant tumor

项目摘要

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 (IDH1/2) 的杂合突变是高达 20% 的新诊断 AML 患者中存在 IDH1/2 酶，可将异柠檬酸转化为 α-酮戊二酸。三羧酸 (TCA) 循环中的 (aKG) 突变赋予新形态的酶活性，从而导致 aKG 转化为致癌代谢物 2-羟基戊二酸 (2HG) 会竞争性抑制 aKG-。依赖的双加氧酶，引起深刻的表观遗传改变和造血功能受损 IDH1/2 抑制剂现已获得 FDA 批准用于治疗 AML，尽管这些药物通常未被批准。治愈，完全缓解 (CR) 率和中位总生存 (OS) 范围在 20-30% 之间此外，通常对突变 IDH1/2 抑制剂产生原发性耐药和获得性耐药。这些药物作为单一疗法无法治愈的部分原因是它们的作用。具体来说，这些药物通过诱导分化以细胞抑制方式发挥作用，突出显示的是，突变型 IDH1/2 克隆在患者体内持续存在，甚至是那些获得多数治疗的患者 a CR.这些数据强调需要开发针对 IDH1/2 突变 AML 的替代方法。我们的团队最近发现 IDH1/2 突变会诱导 DNA 损伤反应 (DDR) 缺陷，从而导致 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。 2HG 诱导的赖氨酸脱甲基酶 KDM4B 抑制导致组蛋白 3 异常高甲基化赖氨酸 9 (H3K9) 位于 DNA 断裂周围的位点，掩盖了对于 DNA 断裂至关重要的局部 H3K9 三甲基化信号同源重组 (HR) 的正确执行，这是 DNA 双链断裂 (DSB) 修复的关键我们还将这些发现扩展到其他产生肿瘤代谢物的 TCA 基因突变。我们统称为“致癌代谢物诱导的 BRCA 性”。我们的工作表明，致癌代谢物-。诱导的 BRCAness 与肿瘤类型无关，我们现在直接将这项工作转化为多种临床试验，目前正在测试 PARP 抑制剂对 IDH1/2 突变癌症（包括 AML）的功效（NCT03953898；PRIME 试验；PI：Prebet）。目前已明确 IDH1/2 突变会导致 AML 中的 DDR 缺陷，在此我们建议研究：(a) AML 中常见、同时发生的突变对相关 DDR 缺陷的影响，这将是对于治疗靶向至关重要；(b) 哪种 DDR 抑制剂最有效，以及是否与其他治疗 AML 的全身药物将提高疗效；以及 (c) 我们基于 DDR 抑制剂的疗效这些研究表明，策略将有效对抗具有内在或获得性治疗耐药性的肿瘤。有可能为新诊断和复发的 IDH1/2 建立全新的治疗方法突变 AML，利用我们团队发现的 DDR 缺陷，重点关注 FDA 批准的药物。获得批准或在临床试验中，我们的工作可以快速转化为临床。