Exploiting Mutant IDH1/2-induced Homologous Recombination Defects in Cancer

利用突变 IDH1/2 诱导的癌症同源重组缺陷

• 批准号: 9926846
• 负责人: Ranjit Bindra
• 金额: $ 39.26万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926846
• 关键词: Affect; Automobile Driving; Binding; Brain Neoplasms; Cell Line; Cells; Clinical Trials; Combined Modality Therapy; Coupled; DNA Damage; DNA Repair; Data; Defect; Dioxygenases; Double Strand Break Repair; Enzyme Inhibition; Evaluation; FDA approved; Fumarates; Future; Genetic; Glioma; Goals; Hypoxia; In Vitro; Induced Mutation; Isocitrate Dehydrogenase; Kinetics; Laboratories; Left; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Modernization; Mutation; Oncogenic; Oncology; Operative Surgical Procedures; Pathologic Processes; Patients; Phenotype; Phosphotransferases; Poly(ADP-ribose) Polymerases; Procarbazine; Process; Production; Proteins; Publishing; RNA; Radiation Tolerance; Radiation therapy; Regimen; Succinates; Testing; Therapeutic; Tissues; Translating; Treatment Protocols; Vincristine; Work; alpha ketoglutarate; base; biomarker-driven; chemotherapy; clinical application; clinically relevant; efficacy testing; enantiomer; experimental study; homologous recombination; in vivo; inhibitor/antagonist; mutant; neoplastic cell; novel; novel strategies; outcome forecast; precision medicine; response; small molecule; targeted treatment; temozolomide; tumor; tumor progression; tumor xenograft

Only a handful of therapies are available for treatment in the front-line for glioma: radiotherapy, temozolomide, and PCV (procarbazine, CCNU, and vincristine). These therapies have not changed in over 3 decades, and in most cases they are not curative, nor are they targeted to the underlying mutations driving these tumors. 2-Hydroxyglutarate (2HG) exists as two enantiomers, R-2HG and S-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase-1 and -2 (IDH1/2) mutations, while the latter is produced under pathologic process such as hypoxia. Our laboratory recently discovered that IDH1/2 mutations induce a homologous recombination (HR) defect which renders tumor cells exquisitely sensitive to Poly (ADP-Ribose) polymerase (PARP) inhibitors. Remarkably, this “BRCAness” phenotype can be completely reversed by small molecule mutant IDH1 inhibitors, and it can be entirely recapitulated by treatment with either 2HG enantiomer in cells with intact IDH1/2. We demonstrated IDH1-dependent PARP inhibitor sensitivity in a range of clinically relevant models, including primary patient-derived glioma cells in vitro and genetically-matched tumor xenografts in vivo. These findings directly challenge the current therapeutic strategy to block IDH1/2 mutant function by direct inhibition, and they instead provide a novel approach to treat these tumors with DNA repair inhibitors. Furthermore, our results uncover an unexpected link between oncometabolites, DNA repair and genetic instability. Based on the preliminary data presented above, our central hypothesis is that IDH1/2-mutant tumors harbor intrinsic double-strand break (DSB) repair defects, which can be exploited for a therapeutic gain. The overall goals of this application are (1) to understand how R-2HG and related oncometabolites, which are induced by IDH1/2 mutations and other processes, suppress DSB repair, (2) how DSB repair specifically is affected by these oncometabolites, and (3) the most effective way to exploit this defect using DNA repair inhibitor-based treatment regimens. In Aim 1 of this application, we will test the hypothesis that specific αKG- dependent dioxygenases mediate the observed phenotype of oncometabolite-induced DSB repair suppression. In Aim 2, we will perform a comprehensive evaluation of key nodes in the DNA damage response network, in order to localize the exact mechanism(s) of action by which DSB repair is suppressed. Finally, in Aim 3, we will test the hypothesis that the oncometabolite-induced DSB repair defect can be targeted by combination treatment with DNA repair inhibitors and DNA damaging agents. The long term goal of this study is to translate our novel findings into a clinical trial, in which we will test the efficacy of the combination therapies that are identified in this proposal. This trial would be tissue-agnostic and biomarker-driven, focusing on tumors that produce high levels of oncometabolites, which can be exploited with DNA repair inhibitor-based regimens.

只有少数几种疗法可用于神经胶质瘤的一线治疗：放射疗法、 替莫唑胺和 PCV（丙卡巴肼、CCNU 和长春新碱）。这些疗法在超过3年的时间里没有改变 几十年来，在大多数情况下，它们没有治疗作用，也不是针对驱动的潜在突变 这些肿瘤。 2-羟基戊二酸 (2HG) 以两种对映体形式存在：R-2HG 和 S-2HG，两者都是 通过对 α-酮戊二酸 (αKG) 依赖性双加氧酶的抑制作用参与肿瘤进展。 前者是一种致癌代谢物，由异柠檬酸赋予的新形态活性诱导 脱氢酶-1和-2（IDH1/2）突变，而后者是在病理过程中产生的，例如 缺氧。我们实验室最近发现IDH1/2突变诱导同源重组（HR） 这种缺陷使得肿瘤细胞对聚（ADP-核糖）聚合酶（PARP）抑制剂极其敏感。 值得注意的是，这种“BRCAness”表型可以被小分子突变体 IDH1 完全逆转 抑制剂，并且可以通过用任一 2HG 对映异构体在具有完整的细胞中处理来完全重现。 IDH1/2。我们在一系列临床相关模型中证明了 IDH1 依赖性 PARP 抑制剂敏感性， 包括体外原代患者来源的神经胶质瘤细胞和体内基因匹配的肿瘤异种移植物。这些 研究结果直接挑战了当前通过直接抑制来阻断 IDH1/2 突变功能的治疗策略， 相反，他们提供了一种用 DNA 修复抑制剂治疗这些肿瘤的新方法。此外，我们的 结果揭示了肿瘤代谢物、DNA 修复和遗传不稳定性之间的意外联系。 基于上述初步数据，我们的中心假设是 IDH1/2 突变肿瘤 具有内在的双链断裂（DSB）修复缺陷，可以利用它来获得治疗效果。这 该应用程序的总体目标是 (1) 了解 R-2HG 和相关肿瘤代谢物如何 由 IDH1/2 突变和其他过程诱导，抑制 DSB 修复，(2) DSB 修复具体是如何进行的 受这些肿瘤代谢物的影响，以及 (3) 利用 DNA 修复来利用这种缺陷的最有效方法 基于抑制剂的治疗方案。在本应用的目标 1 中，我们将测试特定 αKG- 依赖的双加氧酶介导观察到的癌代谢物诱导的 DSB 修复抑制的表型。 在目标2中，我们将对DNA损伤响应网络中的关键节点进行综合评估， 为了定位抑制 DSB 修复的确切作用机制。最后，在目标 3 中，我们将 检验肿瘤代谢物诱导的 DSB 修复缺陷可以通过组合靶向的假设 DNA修复抑制剂和DNA损伤剂治疗。这项研究的长期目标是 将我们的新发现转化为临床试验，我们将在其中测试联合疗法的功效 本提案中确定的内容。该试验将与组织无关且由生物标志物驱动，重点关注肿瘤 产生高水平的肿瘤代谢物，可用于基于 DNA 修复抑制剂的治疗方案。