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

• 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
• 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' 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' 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; 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' 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' 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

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.

项目摘要 弥漫性大B细胞淋巴瘤（DLBCL），最常见的非霍奇金淋巴瘤（NHL）类型高度 侵略性和欲望抗逆转录病毒仍然是与癌症相关死亡的主要原因 与艾滋病毒。值得注意的是，多达90％的HIV-DLBCL对引起癌症的爱泼斯坦 - 巴尔病毒（EBV）呈阳性。那， 了解EBV对癌症的贡献对于发现新的治疗方法至关重要。 癌细胞需要DNA修复，但是EBV如何参与和重塑细胞DNA修复是一种毫无疑问的 区域。我们对EBV-CASTER细胞和EBV转化的人B细胞（淋巴母细胞系）的研究，后者 免疫抑制宿主中由EBV驱动的淋巴瘤的重要模型，在STAT3上收敛。一个 癌蛋白，STAT3经常在癌症中激活。几项研究还表明EBV+ HIV-DLBCL Janus激酶（JAK）-STAT3途径中经常暴露于激活突变。我们发现EBV 激活STAT3以规避S相检查点屏障，从而确保细胞增殖 过程，失去同源重组（HR），可修复DNA双链断裂（DSB）。结果，EBV- 转化和癌细胞依赖于其他形式的DNA修复，特别是容易出错 微学介导的最终连接（MMEJ）的修复类型。这会产生一种治疗性脆弱性 致命剂，否则对具有完整HR的细胞无毒。 PARP [Poly（ADP-核糖）聚合酶] 抑制剂是靶向mmej的这种合成致死剂之一。确实，我们发现EBV转换已有 癌细胞非常容易受到靶向PARP和MMEJ特异性DNA聚合酶的MMEJ抑制剂 polθ。支持这种对MMEJ的依赖性，EBV转化的细胞表现出MMEJ的全基因组疤痕 与EBV相比 肿瘤； POLQ编码Polθ。此外，通过对数百个癌细胞系的多媒体分析，我们有 确定了与STAT3相关的基因表达签名，该签名指向STAT3和STAT3和 依赖MMEJ修复，同时预测了对合成致命疗法的敏感性。 现在，我们建议调查EBV如何使用JAK-STAT3途径重塑DNA修复并渲染EBV+ HIV-DLBCL容易受到合成致命治疗靶向的影响。使用细胞系，Xenographictic和患者衍生 NCI AIDS和癌症标本资源（ACSR）的EBV+＆EBV- HIV-DLBCL，我们研究了链接 在EBV+ HIV-DLBCL（AIM 1）中的JAK-STAT3途径和DSB修复之间 STAT3依赖性DNA修复缺乏可杀死EBV+ HIV-DLBCL（AIM 2）。 这些研究专门针对PAR-21-348，通过识别机制并产生新的范式 揭示EBV如何对NHL贡献。从长远来看，这些机械洞察力将发现新颖的漏洞 并能够预测对合成致命疗法的反应，以改善EBV+ DLBCL的结果 患有艾滋病毒的人。