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: 10599232
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599232
• 关键词: Adenosine Diphosphate Ribose; Affect; Antibody Affinity; B-Cell Activation; B-Lymphocytes; 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; Diffuse Lymphoma; 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; 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(ADP-ribose) Polymerase Inhibitor; 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; 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）是最常见的非霍奇金淋巴瘤（NHL）的亚型，具有 每年〜25,000个新案件。尽管治疗的改善明显改善，但其中约有一半的患者屈服于 他们的疾病。因此，非常需要新的治疗方法来改善DLBCL患者的' 生存。在这里我们表明，在DLBCL细胞中，仅LIM结构域2（LMO2）蛋白抑制DNA双链 通过同源重组（HR）破裂（DSB）修复，导致HR功能。此HR功能 乳腺癌，卵巢和cast割前列腺癌中的BRCA1/2突变。因此，我们 证明LMO2在用聚腺苷处理后易于DLBCL细胞在合成的杀伤力中 双磷酸盐 核糖） 聚合酶 1 和 2 （PARP1/2） 抑制剂。长期目标是证明 PARPI活性可以改善表达DLBCL的LMO2患者的结果。总体目标 建议是确定LMO2通过HR抑制DNA断裂的修复的机制 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。中心假设是通过LMO2诱导的HR抑制DNA修复将使DLBCL敏感 肿瘤至PARP1/2抑制剂。该项目的理由是人力资源和失败的缺陷 到 维修 DSB 生产 原因 坚硬的 在复制过程中，PARP1/2抑制剂确实 在复制过程中，有毒DSB的积累已被利用用于治疗HR缺乏剂 肿瘤。 可能导致基因组不稳定性和/或细胞死亡。 我们的初步数据表明，在DLBCL细胞中，LMO2抑制了HR途径。因此，我们 提出LMO2对HR的抑制作用将使DLBCL肿瘤对PARP1/2敏感 抑制剂。 在 命令 到 测试 这 中央 目标： 低血分并确定LMO2控制DNA修复的机制，我们提出了三个特定的特异性 1）确定DLBCL中HR的LMO2介导的抑制作用的机制； 2）确定LMO2如何影响 正常B细胞​​中的免疫球蛋白类开关重组； 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，与当前的现状相去甚远 DLBCL中PARP1/2抑制剂的治疗活性，代表了一种有效的新治疗策略 将扩大现有的武器库针对这种淋巴瘤。提出的研究很重要，因为它是 有望为开发一种新型治疗方法提供强有力的科学理由 DLBCL基于PARP1/2抑制剂，可能会改变DLBCL患者的当前治疗 改善他们的结果。

项目成果

Conditional expression of HGAL leads to the development of diffuse large B-cell lymphoma in mice.

• DOI: 10.1182/blood.2020004996
• 发表时间: 2020-09
• 期刊: Blood
• 影响因子: 20.3
• 作者: Javier Raboso-Gallego;Ana Casado-García;Xiaoyu Jiang;Marta Isidro-Hernández;A. Gentles;Shuchun Zhao;Y. Natkunam;O. Blanco;Verónica Domínguez;Belén Pintado;D. Alonso-López;J De Las Rivas;Carolina Vicente-Dueñas;I. Lossos;I. Sánchez-García

Human Germinal Center-associated Lymphoma (HGAL) Is a Reliable Marker of Normal and Neoplastic Follicular Helper T Cells Including Angioimmunoblastic T-Cell Lymphoma.

人类生发中心相关淋巴瘤 (HGAL) 是正常和肿瘤性滤泡辅助 T 细胞（包括血管免疫母细胞 T 细胞淋巴瘤）的可靠标志物。

• DOI: 10.1097/pas.0000000000001852
• 发表时间: 2021
• 期刊: The American journal of surgical pathology
• 作者: Koo,Matthew;Zhang,Jingjing;Tan,Brent;Kurzer,Jason;Gratzinger,Dita;Zhao,Shuchun;Suarez,Carlos;Lossos,IzidoreS;Warnke,RogerA;Natkunam,Yasodha
• 通讯作者: Natkunam,Yasodha