Synthetic lethal targeting of EBV-positive diffuse large B cell lymphomas in persons living with HIV

HIV 感染者 EBV 阳性弥漫性大 B 细胞淋巴瘤的合成致死靶向

基本信息

批准号：
10703446
负责人：
SUMITA BHADURI-MCINTOSH
金额：
$ 75.07万
依托单位：
UNIVERSITY OF FLORIDA
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：
2022-09-12 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10703446
关键词：
Acquired Immunodeficiency Syndrome Address Anti-Retroviral Agents Area B-Lymphocytes Cancer Etiology Cancer cell line Cell Line Cell Proliferation Cells Cessation of life Cicatrix DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Disorder DNA-Directed DNA Polymerase Data Set Dependence Disease Double Strand Break Repair Ensure Epstein-Barr Virus Infections Epstein-Barr Virus-Related Lymphoma Exhibits FDA approved Gene Expression Profile Gene Expression Profiling Genome Goals HIV Herpesviridae Human Human Herpesvirus 4 Immunocompromised Host Impairment Individual Investigation Janus kinase Link Malignant Neoplasms Malignant neoplasm of ovary Mediating Modeling Mutation Non-Hodgkin&apos s Lymphoma Oncogenic Oncogenic Viruses Oncoproteins Pathway interactions Patients Persons Pharmaceutical Preparations Poly(ADP-ribose) Polymerase Inhibitor Polymerase Predisposition Process Proliferating Property Regimen Research S phase Shapes Stat3 protein Testing Therapeutic Therapeutic Agents Transcript Translating Xenograft Model Xenograft procedure antiretroviral therapy brca gene cancer cell cancer specimen resource cell transformation clinical risk clinically actionable drug action gene regulatory network genome-wide high risk homologous recombination improved outcome in vivo in vivo Model inhibitor innovation insight large cell Diffuse non-Hodgkin&apos s lymphoma lymphoblastoid cell line malignant breast neoplasm multiple omics novel novel therapeutic intervention personalized medicine predicting response predictive marker predictive signature repaired response targeted agent therapeutic target transcription factor transforming virus tumor

项目摘要

PROJECT SUMMARY Diffuse large B-cell lymphoma (DLBCL), the commonest type of non-Hodgkin lymphoma (NHL), is highly aggressive and despite antiretrovirals continues to be a leading cause of cancer-related death in persons living with HIV. Notably, up to 90% of HIV-DLBCL are positive for the cancer-causing Epstein-Barr virus (EBV). Thus, understanding how EBV contributes to cancer is essential to discovering new therapeutic approaches. Cancer cells require DNA repair but how EBV engages and reshapes cellular DNA repair is an underexplored area. Our studies on EBV-cancer cells and EBV-transformed human B cells (lymphoblastoid cell lines), the latter an important model of EBV-driven lymphomas in immunosuppressed hosts, converge on STAT3. An oncoprotein, STAT3 is frequently activated in cancer. Several studies have also shown that EBV+ HIV-DLBCL frequently exhibit activating mutations in the Janus kinase (JAK)-STAT3 pathway. We have found that EBV activates STAT3 to circumvent the S phase checkpoint barrier, thereby ensuring cell proliferation but in the process, loses homologous recombination (HR) that repairs DNA double strand breaks (DSB). As a result, EBV- transformed and cancer cells become dependent on other forms of DNA repair, in particular, the error-prone microhomology-mediated end-joining (MMEJ) type of repair. This creates a therapeutic vulnerability to synthetic lethal agents that would otherwise be non-toxic to cells with intact HR. PARP [poly (ADP-ribose) polymerase] inhibitors are among such synthetic lethal agents that target MMEJ. Indeed, we find that EBV-transformed and cancer cells are highly susceptible to MMEJ inhibitors that target PARP and the MMEJ-specific DNA polymerase, POLθ. Supporting this dependence on MMEJ, EBV-transformed cells exhibit genome-wide scars of MMEJ repair, and, EBV+ HIV-DLBCL display higher abundance of STAT3 and POLQ transcripts compared to EBV- tumors; POLQ encodes POLθ. Further, by multiomic analyses of several hundred cancer cell lines, we have identified a STAT3-related gene expression signature that points to a mechanistic link between STAT3 and reliance on MMEJ repair while predicting susceptibility to synthetic lethal therapies. We now propose to investigate how EBV uses the JAK-STAT3 pathway to reshape DNA repair and render EBV+ HIV-DLBCL vulnerable to synthetic lethal therapeutic targeting. Using cell lines, xenografts, and patient-derived EBV+ & EBV- HIV-DLBCL from the NCI AIDS and Cancer Specimen Resource (ACSR), we investigate the link between JAK-STAT3 pathway and DSB repair in EBV+ HIV-DLBCL (Aim 1) and synthetic-lethally exploit JAK- STAT3-dependent DNA repair deficiency to kill EBV+ HIV-DLBCL (Aim 2). These studies specifically address PAR-21-348 by identifying mechanisms and generating new paradigms to reveal how EBV contributes to NHL. In the long-term, these mechanistic insights will uncover novel vulnerabilities and enable the prediction of responses to synthetic lethal therapies to improve outcomes for EBV+ DLBCL in persons living with HIV.

项目概要弥漫性大 B 细胞淋巴瘤 (DLBCL) 是最常见的非霍奇金淋巴瘤 (NHL) 类型，发病率很高尽管抗逆转录病毒药物具有侵略性，但仍然是生活中癌症相关死亡的主要原因值得注意的是，高达 90% 的 HIV-DLBCL 的致癌 Epstein-Barr 病毒 (EBV) 呈阳性。了解 EBV 如何导致癌症对于发现新的治疗方法至关重要。癌细胞需要 DNA 修复，但 EBV 如何参与和重塑细胞 DNA 修复尚不清楚我们对 EBV 癌细胞和 EBV 转化的人类 B 细胞（淋巴母细胞系）的研究，后者。免疫抑制宿主中 EBV 驱动的淋巴瘤的一个重要模型，集中在 STAT3 上。一些研究还表明，癌蛋白 STAT3 在癌症中经常被激活。我们发现 EBV 经常表现出 Janus 激酶 (JAK)-STAT3 通路的激活突变。激活STAT3，绕过S期检查点屏障，保证细胞增殖，从而保证细胞增殖，但在过程中，失去修复 DNA 双链断裂 (DSB) 的同源重组 (HR)，结果是 EBV-。转化后的癌细胞变得依赖于其他形式的 DNA 修复，特别是容易出错的修复微同源介导的末端连接（MMEJ）类型的修复这造成了合成的治疗脆弱性。对具有完整 HR 的细胞无毒的致死剂。事实上，我们发现 EBV 可以转化并抑制 MMEJ 的合成致死剂。癌细胞对针对 PARP 和 MMEJ 特异性 DNA 聚合酶的 MMEJ 抑制剂高度敏感， POLθ 支持这种对 MMEJ 的依赖，EBV 转化的细胞表现出全基因组的 MMEJ 疤痕。与 EBV- 相比，EBV+ HIV-DLBCL 显示出更高丰度的 STAT3 和 POLQ 转录本此外，通过对数百个癌细胞系的多组学分析，我们得到了 POLQ 编码的 POLθ。确定了 STAT3 相关基因表达特征，该特征表明 STAT3 和依赖 MMEJ 修复，同时预测对合成致死疗法的敏感性。我们现在建议研究 EBV 如何利用 JAK-STAT3 途径重塑 DNA 修复并呈现 EBV+ HIV-DLBCL 容易受到使用细胞系、异种移植物和患者来源的合成致死治疗靶向的影响。来自 NCI 艾滋病和癌症标本资源 (ACSR) 的 EBV+ 和 EBV- HIV-DLBCL，我们调查了链接 JAK-STAT3 通路与 EBV+ HIV-DLBCL 中 DSB 修复之间的关系（目标 1）以及合成致死利用 JAK- STAT3 依赖性 DNA 修复缺陷可杀死 EBV+ HIV-DLBCL（目标 2）。这些研究通过确定机制并生成新的范式来专门解决 PAR-21-348 揭示 EBV 如何对 NHL 做出贡献从长远来看，这些机制见解将揭示新的漏洞。并能够预测对合成致死疗法的反应，以改善 EBV+ DLBCL 的治疗结果艾滋病毒感染者。