Overcoming Drug Resistance Driven by BCL10 Mutations in Diffuse Large B Cell Lymphoma

克服弥漫性大 B 细胞淋巴瘤中 BCL10 突变导致的耐药性

• 批准号: 10653228
• 负责人: Caroline Alice Coughlin
• 金额: $ 5.27万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653228
• 关键词: Agammaglobulinaemia tyrosine kinase; American; Automobile Driving; B lymphoid malignancy; B-Cell Activation; B-Lymphocytes; BCL10 gene; BCL6 gene; Biochemical; Biological; Biological Markers; Cell Line; Cells; Chronic Lymphocytic Leukemia; Classification; Clinical; Clinical Trials; Complex; Cyclophosphamide; Data; Dependence; Diagnosis; Disease; Doxorubicin; Drug Targeting; Drug resistance; Exhibits; Genetic; Genetic Recombination; Goals; Hematologic Neoplasms; Immuno-Chemotherapy; In Vitro; Incidence; Intrinsic factor; Laboratories; Lead; Lymphoma; Lymphoma cell; Lymphomagenesis; MAPK8 gene; Mature B-Lymphocyte; Mediating; Mission; Modeling; Molecular; Mucosa- associated lymphoid tissue lymphoma translocation protein-1; Mus; Mutate; Mutation; NF-kappa B; Nature; Non-Hodgkin' s Lymphoma; Oncogenic; Organ; Outcome; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Physicians; Prednisone; Prognosis; Public Health; Recurrence; Refractory; Relapse; Research; Resistance; Role; Scientist; Signal Pathway; Signal Transduction; Survival Analysis; System; Testing; Therapeutic; Therapeutic Studies; Tyrosine Kinase Inhibitor; Vincristine; alternative treatment; biomarker identification; career; clinical decision-making; clinical heterogeneity; disorder subtype; experimental study; genetic regulatory protein; human disease; improved; improved outcome; in vivo; in vivo Model; innovation; large cell Diffuse non-Hodgkin' s lymphoma; mouse model; novel; novel therapeutic intervention; novel therapeutics; overexpression; pre-clinical; resistance mechanism; response; response biomarker; rituximab; skills; small molecule; synergism; targeted treatment; therapeutic target; treatment response; treatment strategy; tumor

Project Summary Diffuse large B cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma and the most common hematologic malignancy. DLBCL exhibits significant molecular and clinical heterogeneity, yet all patients are treated with standard chemoimmunotherapy. As such, there is a strong clinical need to identify biomarkers of drug response and novel therapies to improve patient outcomes. BCL10 mutations are prevalent among DLBCL subtypes and recurrent mutations frequently truncate the BCL10 protein’s regulatory C-terminus. BCL10 is a core component of the CARD11 (CARMA1)-BCL10-MALT1 complex, which activates downstream oncogenic pathways like JNK and NF-kB in DLBCL; however, the mechanisms by which BCL10 mutations promote lymphomagenesis in DLBCL are poorly understood. Recent results implicate BCL10 mutations in the induction of NF-kB signaling and MALT1 protease activity and Bruton’s Tyrosine Kinase inhibitor (BTKi) resistance. The overall objective is to understand the role of BCL10 mutations in DLBCL, to determine mechanisms of drug resistance and to identify alternative treatment strategies for patients with these mutations. The central hypothesis that BCL10 mutations are activating in nature, driving lymphomagenesis and resistance to BTKis, will be tested through the following specific aims: 1) Understand the role of BCL10 mutations in lymphomagenesis using genetically accurate in vivo models, and 2) Identify alternative therapeutic targets to overcome drug resistance mediated by BCL10 mutations. Aim 1 will characterize survival and tumor incidence of a novel murine model generated in the lab containing an inducible BCL10 truncation mutation expressed on the ROSA26 locus of C57BL/6J mice. The model mimics human disease through B-cell-specific activation of BCL10 mutations using Cre-recombination and will also be crossed with mice overexpressing BCL6, which occurs in context with BCL10 mutations. Aim 2 will identify compounds to attack BCL10 mutated cells alone or in combination with BTKis by implementing small molecule synergy screens that target the BCR, NF- kB and parallel signaling pathways. The expected outcome is the creation of genetically accurate in vivo models of BCL10 mutations to understand their lymphomagenic potential, to define BCL10 as a biomarker of BTKi resistance, and to identify novel, targetable dependencies induced by BCL10 mutations. The proposed research is significant because it will uncover mechanisms of lymphomagenesis, identify biomarkers to guide clinical decision-making in DLBCL and discover potential drug targets to overcome resistance or synergize with existing therapies. Also, these studies are innovative because the described mouse model will be the first to characterize BCL10 mutations in vivo and will provide a novel context to study lymphomagenesis and drug resistance driven by BCL10 mutations. Overall, this research will have positive impacts as identifying BCL10 as a biomarker for response to therapy and determining a therapeutic strategy for patients with BCL10 mutations will guide treatment options and improve outcomes in DLBCL patients.

项目概要 弥漫性大 B 细胞淋巴瘤 (DLBCL) 是一种侵袭性非霍奇金淋巴瘤，也是最常见的淋巴瘤 血液系统恶性肿瘤。 DLBCL 表现出显着的分子和临床异质性，但所有患者均 采用标准化学免疫疗法进行治疗。因此，临床迫切需要鉴定生物标志物 药物反应和新疗法可改善患者的治疗效果。 BCL10 突变在 DLBCL 中普遍存在 亚型和反复突变经常会截短 BCL10 蛋白的调节性 C 末端。 BCL10 是 CARD11 (CARMA1)-BCL10-MALT1 复合物的核心成分，可激活下游致癌物质 DLBCL 中的 JNK 和 NF-kB 等通路；然而，BCL10突变促进的机制 DLBCL 的淋巴瘤发生机制尚不清楚。最近的结果表明诱导过程中 BCL10 突变 NF-kB 信号传导和 MALT1 蛋白酶活性以及布鲁顿酪氨酸激酶抑制剂 (BTKi) 耐药性。这 总体目标是了解 BCL10 突变在 DLBCL 中的作用，以确定药物机制 耐药性并为携带这些突变的患者确定替代治疗策略。中央 假设 BCL10 突变在自然界中被激活，驱动淋巴瘤发生和对 BTKis 的耐药性， 将通过以下具体目标进行测试： 1) 了解 BCL10 突变在 使用遗传精确的体内模型进行淋巴瘤发生，以及 2) 确定替代疗法 目标是克服 BCL10 突变介导的耐药性。目标 1 将描述生存和 实验室生成的含有诱导性 BCL10 截短突变的新型小鼠模型的肿瘤发生率 在 C57BL/6J 小鼠的 ROSA26 基因座上表达。该模型通过 B 细胞特异性来模拟人类疾病 使用 Cre 重组激活 BCL10 突变，并将与过度表达 BCL6 的小鼠杂交， 这发生在 BCL10 突变的背景下。目标 2 将识别攻击 BCL10 突变细胞的化合物 单独或与 BTK 组合，通过实施针对 BCR、NF- 的小分子协同筛选 kB 和平行信号通路。预期结果是创建遗传精确的体内模型 BCL10 突变，以了解其致淋巴瘤的潜力，将 BCL10 定义为 BTKi 的生物标志物 耐药性，并识别由 BCL10 突变引起的新型、可靶向的依赖性。拟议的研究 意义重大，因为它将揭示淋巴瘤发生的机制，识别生物标志物来指导临床 DLBCL 的决策并发现潜在的药物靶点以克服耐药性或与现有药物协同作用 疗法。此外，这些研究具有创新性，因为所描述的小鼠模型将是第一个表征 BCL10 体内突变将为研究淋巴瘤发生和耐药驱动提供新的背景 由 BCL10 突变引起。总体而言，这项研究将产生积极影响，因为将 BCL10 确定为生物标志物 BCL10 突变患者对治疗的反应和确定治疗策略将指导 治疗选择并改善 DLBCL 患者的预后。