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）是一种侵略性的非霍奇金淋巴瘤，是最常见的 血液系统恶性肿瘤。 DLBCL表现出明显的分子和临床异质性，但所有患者均为 用标准化学免疫疗法治疗。因此，有很大的临床需要识别 药物反应和新的疗法以改善患者预后。 BCl10突变在DLBCL中普遍存在 亚型和复发突变经常截断Bcl10蛋白的调节性C末端。 Bcl10是 Card11（CARMA1）-BCl10-MALT1复合物的核心成分，该复合物激活下游致癌 DLBCL中的JNK和NF-KB等途径；但是，Bcl10突变促进的机制 DLBCL中的淋巴作用知之甚少。最近的结果暗示了诱导中的Bcl10突变 NF-KB信号传导和MALT1蛋白酶活性以及Bruton的酪氨酸激酶抑制剂（BTKI）抗性。这 总体目的是了解Bcl10突变在DLBCL中的作用，以确定药物的机制 抗性并确定这些突变患者的替代治疗策略。中央 假设Bcl10突变在本质上正在激活，驱动淋巴作用和对BTKIS的抗性， 将通过以下特定目的进行测试：1）了解Bcl10突变在 淋巴作用使用一般准确的体内模型，2）识别替代治疗 克服由Bcl10突变介导的耐药性的靶标。 AIM 1将以生存为特征和 在实验室中产生的新型鼠模型的肿瘤发生率，该模型包含诱导型Bcl10截断突变 在C57BL/6J小鼠的ROSA26基因座上表达。该模型通过B细胞特异性模仿人类疾病 使用Cre-Recombination激活Bcl10突变，也将与过表达Bcl6的小鼠交叉， 这是在Bcl10突变的上下文中发生的。 AIM 2将识别攻击Bcl10突变细胞的化合物 通过实现针对BCR，NF-的小分子协同屏幕，单独或与BTKI结合 KB和并行信号通路。预期的结果是创建一般准确的体内模型 Bcl10突变的理解其淋巴细胞增强潜力，以将Bcl10定义为BTKI的生物标志物 抗性，并确定由Bcl10突变引起的新型，可靶向的依赖性。拟议的研究 之所以重要，是因为它会发现淋巴作用的机制，鉴定生物标志物以指导临床 DLBCL的决策，发现潜在的药物靶标，以克服抗药性或与现有 疗法。而且，这些研究具有创新性，因为所述的鼠标模型将是第一个表征的。 体内Bcl10突变，将提供一种新的背景来研究淋巴作用和耐药性驱动 由Bcl10突变。总体而言，这项研究将对BCL10识别为生物标志物的积极影响 对治疗的反应并确定BCL10突变患者的理论策略将指导 治疗选择并改善DLBCL患者的预后。