Identify the Mechanisms of LMO2-Mediated Inhibition of Homologous Recombination and Establish PARP-Targeted Synthetic Lethality as a New Therapy for DLBCL

确定 LMO2 介导的同源重组抑制机制并建立 PARP 靶向合成致死作为 DLBCL 的新疗法

• 批准号: 9900766
• 负责人: IZIDORE S LOSSOS
• 金额: $ 35.95万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900766
• 关键词: Address; Affect; Antibody Affinity; B-Cell Activation; B-Lymphocytes; BCL2 gene; BRCA1 gene; Biological; Biological Markers; Breast; Cell Death; Cells; Chemotherapy-Oncologic Procedure; Chromosomal translocation; Classification; Complex; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Inhibition; Data; Development; Disease; Double Strand Break Repair; Doxorubicin; Endothelium; Failure; Frequencies; Functional disorder; Genomic Instability; Goals; Hematopoietic; Immune response; Immunoglobulin Class Switching; Immunoglobulin Switch Recombination; In Vitro; Lead; Lymphoma; Lymphoma cell; Malignant Neoplasms; Mediating; Mission; Modeling; Molecular; Mutagens; Mutation; Non-Hodgkin' s Lymphoma; Oncogenic; Outcome; Ovarian; Pathway interactions; Patient-Focused Outcomes; Patients; Phenocopy; Physiological; Physiological Processes; Play; Poly Adenosine Diphosphate Ribose; Polymerase; Process; Public Health; Research; Rhombotin 2; Role; Site; Solid; Solid Neoplasm; Structure of germinal center of lymph node; Testing; Therapeutic; Therapeutic Uses; United States National Institutes of Health; Work; base; castration resistant prostate cancer; chemotherapy; disability; homologous recombination; improved; improved outcome; in vivo; inhibitor/antagonist; innovation; large cell Diffuse non-Hodgkin' s lymphoma; novel; novel marker; novel therapeutic intervention; novel therapeutics; p53-binding protein 1; pre-clinical; response; treatment response; tumor

PROJECT SUMMARY/ ABSTRACT Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), with ~25,000 new cases yearly. Despite marked improvement in therapy, about half of these patients succumb to their disease. Therefore, there is a strong need for new therapeutic approaches to improve DLBCL patients' survival. Here we show that in DLBCL cells the LIM domain-only 2 (LMO2) protein inhibits DNA double-strand break (DSB) repair via homologous recombination (HR), resulting in HR-dysfunction. This HR-dysfunction phenocopies BRCA1/2 mutations in breast, ovarian and castration-resistant prostate cancers. Accordingly, we show that LMO2 predisposes DLBCL cells to synthetic lethality upon treatment with Poly(adenosine diphosphate ribose) polymerase 1 and 2 (PARP1/2) inhibitors. The long-term goal is to demonstrate that PARPi activity may improve outcome of patients with LMO2 expressing DLBCL. The overall objectives of this proposal are to determine the mechanisms by which LMO2 inhibits the repair of DNA breaks via HR and whether LMO2 expression levels can be exploited as a biomarker for sensitivity of DLBCL to PARP1/2 inhibitors. The central hypothesis is that inhibition of DNA repair via HR induced by LMO2 will sensitize DLBCL tumors to PARP1/2 inhibitors. The rationale for this project is that deficiency in HR and failure to repair DSBs produced cause solid during replication Indeed, PARP1/2 inhibitors that the accumulation of toxic DSBs during replication, had been exploited for the treatment of HR-deficient tumors. can lead to genomic instability and/or cell death. Our preliminary data showed that in DLBCL cells LMO2 inhibits the HR pathway. Thus, we propose that inhibition of HR by LMO2 will sensitize DLBCL tumors to PARP1/2 inhibitors. In order to test the central aims : hypotesis and determine the mechanims by which LMO2 controls DNA repair we propose three specific 1)Identify mechanism(s) of LMO2-mediated inhibition of HR in DLBCL; 2) Determine how LMO2 affects immunoglobulin class switch recombination in normal B-cells; and 3) Demonstrate that DLBCL expressing LMO2 are sensitive to PARP1/2 inhibition. The proposed research is innovative because it represents a substantive departure from the current status quo by demonstrating that expression of LMO2 protein predicts therapeutic activity of PARP1/2 inhibitors in DLBCL and represents an effective new therapeutic strategy that will broaden the existing arsenal against this lymphoma. The research proposed is significant because it is expected to provide strong scientific justification for the development of a novel therapeutic approach for DLBCL based in PARP1/2 inhibitors that could potentially change the current treatment of DLBCL patients and improve their outcome.

项目概要/摘要 弥漫性大 B 细胞淋巴瘤 (DLBCL) 是非霍奇金淋巴瘤 (NHL) 最常见的亚型， 每年约 25,000 个新病例。尽管治疗取得显着改善，但其中约一半患者死于 他们的疾病。因此，迫切需要新的治疗方法来改善 DLBCL 患者的病情。 生存。在这里，我们表明，在 DLBCL 细胞中，LIM 仅结构域 2 (LMO2) 蛋白抑制 DNA 双链 通过同源重组 (HR) 进行断裂 (DSB) 修复，导致 HR 功能障碍。这种HR功能障碍 表型复制乳腺癌、卵巢癌和去势抵抗性前列腺癌中的 BRCA1/2 突变。据此，我们 表明 LMO2 使 DLBCL 细胞在用聚（腺苷）处理后易于合成致死 二磷酸盐 核糖） 聚合酶 1 和 2 (PARP1/2) 抑制剂。长期目标是证明 PARPi 活性可能会改善表达 LMO2 的 DLBCL 患者的预后。本次活动的总体目标 提案的目的是确定 LMO2 通过 HR 和抑制 DNA 断裂修复的机制 LMO2表达水平是否可以用作DLBCL对PARP1/2敏感性的生物标志物 抑制剂。中心假设是 LMO2 诱导的 HR 抑制 DNA 修复将使 DLBCL 敏感 PARP1/2 抑制剂对肿瘤的影响。该项目的理由是人力资源的不足和失败 到 维修 DSB 产生的 原因 坚硬的 事实上，PARP1/2 抑制剂在复制过程中 复制过程中有毒 DSB 的积累已被用于治疗 HR 缺陷 肿瘤。 可能导致基因组不稳定和/或细胞死亡。 我们的初步数据表明，在 DLBCL 细胞中，LMO2 抑制 HR 通路。因此，我们 提出 LMO2 抑制 HR 将使 DLBCL 肿瘤对 PARP1/2 敏感 抑制剂。 在 命令 到 测试 这 中央 目标： 假设并确定 LMO2 控制 DNA 修复的机制，我们提出了三种具体的 1)确定DLBCL中LMO2介导的HR抑制机制； 2) 确定 LMO2 如何影响 正常 B 细胞中的免疫球蛋白类别转换重组； 3) 证明 DLBCL 表达 LMO2 对 PARP1/2 抑制敏感。拟议的研究具有创新性，因为它代表了 通过证明 LMO2 蛋白的表达预测，与目前的现状有实质性的不同 PARP1/2 抑制剂在 DLBCL 中的治疗活性，代表了一种有效的新治疗策略 将扩大现有的针对这种淋巴瘤的武器库。所提出的研究意义重大，因为它 预计将为开发一种新的治疗方法提供强有力的科学依据 基于 PARP1/2 抑制剂的 DLBCL 可能会改变 DLBCL 患者目前的治疗方法 改善他们的结果。