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: 10378494
• 负责人: IZIDORE S LOSSOS
• 金额: $ 35.23万
• 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/10378494
• 关键词: Address; Affect; Antibody Affinity; B-Cell Activation; B-Lymphocytes; BCL2 gene; BRCA mutations; 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; LMO2 gene; Lead; Lymphoma; Lymphoma cell; Malignant Neoplasms; Mediating; Mission; Modeling; Molecular; Mutagens; 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; 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; 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.

项目摘要/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， 每年约有25,000例新病例。尽管治疗有了显著的进步，这些患者中仍有大约一半死于 他们的病。因此，迫切需要新的治疗方法来改善DLBCL患者的预后。 生死存亡。在这里，我们展示了在DLBCL细胞中，LIM仅结构域2(LMO2)蛋白抑制DNA双链 断裂(DSB)通过同源重组(HR)修复，导致HR功能障碍。这种HR功能障碍 乳腺癌、卵巢癌和去势耐药前列腺癌的表型BRCA1/2突变。因此，我们 结果表明，LMO2使DLBCL细胞在多聚(腺苷)作用下合成死亡 二磷酸盐 核糖) 聚合酶 1 和 2. (PARP1/2) 抑制剂。我们的长期目标是证明 PARPI活性可改善LMO2表达DLBCL患者的预后。这个项目的总体目标是 建议确定LMO2通过HR和DNA2抑制DNA断裂修复的机制 LMO2表达水平能否作为DLBCL对PARP1/2敏感性的生物标志物 抑制剂。中心假说是LMO2通过HR抑制DNA修复将使DLBCL增敏 肿瘤对PARP1/2抑制剂的作用。这个项目理由是人力资源的不足和失败 至 修理 DSB 生产的 原因 实心 事实上，在复制过程中，PARP1/2抑制剂 在复制过程中有毒DSB的积累，已被用于治疗HR缺乏 肿瘤。 可能导致基因组不稳定和/或细胞死亡。 我们的初步数据显示，在DLBCL细胞中，LMO2抑制HR通路。因此，我们 提示LMO2抑制HR可使DLBCL肿瘤对PARP1/2增敏 抑制剂。 在……里面 订单 至 测试 这个 中区 目标： 假设和确定LMO2控制DNA修复的机制，我们提出了三个具体的 1)确定Lmo2抑制DLBCL心率的机制(S)；2)确定Lmo2对DLBCL心率的影响 正常B细胞中的免疫球蛋白类开关重组；3)DLBCL表达 LMO2对PARP1/2抑制敏感。这项拟议的研究具有创新性，因为它代表了 通过证明LMO2蛋白的表达预测了当前的现状，从而实质上偏离了现状 PARP1/2抑制剂对DLBCL的治疗活性，代表了一种有效的新的治疗策略 将扩大现有的针对这种淋巴瘤的武器库。提出的研究具有重要意义，因为它是 有望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可能会改变目前对DLBCL患者和 改善他们的结果。