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: 10314594
• 负责人: Caroline Alice Coughlin
• 金额: $ 5.1万
• 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/10314594
• 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; base; 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.

项目摘要 弥漫性大B细胞淋巴瘤(DLBCL)是一种侵袭性非霍奇金淋巴瘤，是最常见的 恶性血液病。DLBCL表现出显著的分子和临床异质性，但所有患者都是 接受标准的化学免疫治疗。因此，有一个强烈的临床需要，以确定生物标记物 药物反应和新疗法，以改善患者的预后。Bcl10基因突变在DLBCL中的流行 亚型和反复发生的突变经常会截断Bcl10蛋白的调控C末端。Bcl10是一种 CARD11(CARMA1)-Bcl10-MALT1复合体的核心成分，激活下游致癌 DLBCL中的JNK和NF-kB等通路；然而，Bcl10突变促进 DLBCL中的淋巴增生性疾病知之甚少。最近的结果表明，Bcl10基因突变与诱因有关 核因子-kB信号和MALT1酶活性与Bruton‘s酪氨酸激酶抑制物(BTKi)抗性的关系。这个 总体目标是了解bcl10突变在DLBCL中的作用，以确定药物的作用机制 并为具有这些突变的患者确定替代治疗策略。中环 假设Bcl10基因突变在本质上是激活的，导致了淋巴肿大和对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 使用基因准确的体内模型进行淋巴肿大，以及2)确定替代治疗方法 靶向克服Bcl10突变介导的耐药性。目标1将描述生存和 实验室建立的含有可诱导的Bcl10截断突变的新小鼠模型的肿瘤发病率 在C57BL/6J小鼠的rosa26基因座上表达。该模型通过B细胞特异性模拟人类疾病 利用Cre重组激活Bcl10突变，也将与过度表达BCL6的小鼠杂交， 这发生在Bcl10突变的背景下。AIM 2将鉴定攻击Bcl10突变细胞的化合物 通过实施针对BCR、NF-1的小分子协同筛选，单独或与BTKis结合 Kb和并行信号通路。预期的结果是创造出遗传上准确的活体模型 了解Bcl10基因突变的淋巴生成潜能，将Bcl10定义为BTKi的生物标志物 耐药性，并确定由Bcl10突变引起的新的、靶向的依赖关系。拟议的研究 具有重要意义，因为它将揭示淋巴肿大的机制，识别生物标记物来指导临床 DLBCL的决策和发现潜在的药物靶点以克服耐药性或与现有药物协同 治疗。此外，这些研究是创新的，因为所描述的小鼠模型将是第一个表征 Bcl10在体内的突变，将为研究淋巴肿瘤的发生和耐药性驱动提供新的背景 由Bcl10突变引起。总体而言，这项研究将产生积极的影响，将Bcl10确定为 对Bcl10突变患者的治疗反应和确定治疗策略将指导 DLBCL患者的治疗选择和改善预后。