Investigating Bruton's Tyrosine Kinase Dependency in Primary Central Nervous System Lymphoma

研究原发性中枢神经系统淋巴瘤中布鲁顿酪氨酸激酶依赖性

• 批准号: 9981686
• 负责人: Sarah Tang
• 金额: $ 4.55万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981686
• 关键词: Adaptor Signaling Protein; Agammaglobulinaemia tyrosine kinase; B lymphoid malignancy; B-Cell Activation; B-Lymphocytes; Biochemical; Biology; Brain; Brain Neoplasms; Cell Lineage; Cells; Central Nervous System Lymphoma; Cerebrospinal Fluid; Clinical Trials; Combined Modality Therapy; Cues; Dependence; Disease; Disease model; Enhancers; Eye; FDA approved; Frequencies; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Goals; Human; In Vitro; Incidence; Knowledge; Light; Lymphoma cell; Maintenance; Memorial Sloan-Kettering Cancer Center; Modeling; Mus; Mutate; Mutation; Myelogenous; Neoplasm Metastasis; Neuraxis; Non-Hodgkin' s Lymphoma; Nuclear; Pathogenesis; Pathway interactions; Patients; Phase I Clinical Trials; Phase I/II Clinical Trial; Pre-Clinical Model; Progression-Free Survivals; RNA; Receptor Signaling; Receptors, Antigen, B-Cell; Recurrence; Refractory; Relapse; Research; Research Personnel; Resistance; Role; Sampling; Series; Signal Pathway; Signal Transduction; Spinal Cord; Testing; Therapeutic; Tissues; Toll-Like Receptor Pathway; Toll-like receptors; Tyrosine Kinase Inhibitor; Xenograft Model; addiction; aggressive therapy; base; cohort; data modeling; in vivo; large cell Diffuse non-Hodgkin' s lymphoma; member; multiple omics; mutational status; novel; pre-clinical; resistance mechanism; resistance mutation; response; study population; targeted treatment; tumor

Project Summary/Abstract Primary central nervous system lymphoma (PCNSL) is an aggressive disease that presents solely in the central nervous system (CNS). Due to its low disease incidence and the poor quality of patient samples, it has very been challenging to establish preclinical disease models of PCNSL. Therefore, a majority of the knowledge we currently have regarding PCNSL biology and pathogenesis is based on sequencing studies in small patient cohorts, particularly gene expression studies and mutation profiling. Based on gene expression studies, most PCNSL is categorized as diffuse large B cell lymphoma (DLBCL), the most common form of Non-Hodgkin lymphoma. Of the three DLBCL subtypes, PCNSL most resembles the activated B cell-like (ABC) subtype. Based on mutation profiling of PCNSL tumors, PCNSL has recurrent mutations in myeloid differentiation primary response gene 88 (MYD88) (70%) and cluster of differentiation 79B (CD79B) (40%). MYD88 is an adaptor protein associated with Toll-like receptor (TLR), while CD79B is a molecule required for B cell receptor (BCR) signaling. MYD88 and CD79B mutations are also found in ABC DLBCL, though not to the same frequencies as in PCNSL. These mutations are associated with increased activation of nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) in PCNSL. Several targeted therapies have been developed to inhibit this pathway and one example (the first in class) is ibrutinib, a Bruton's Tyrosine Kinase (BTK) inhibitor. BTK is a central signaling node downstream of BCR and TLR. BTK inhibition with ibrutinib has recently been FDA approved for the treatment of several B cell malignancies. Our Phase I/II clinical trial at Memorial Sloan Kettering Cancer Center in relapsed or refractory CNS lymphoma showed that 75% of patients responded to ibrutinib. Though this may appear to simply be a B cell lineage addiction to BTK, we think this is unlikely because some B cell malignancies actually do not respond to ibrutinib. Moreover, of the study patients who responded to ibrutinib, some had mutations in MYD88 and/or CD79B while others did not, indicating that MYD88/CD79B mutation status is insufficient to explain the ibrutinib response. We therefore hypothesize that PCNSL has an overall dependency on BTK that is not due to a B cell lineage addiction. In the proposal, we aim to understand the BTK dependency of PCNSL by assessing the relationship between BTK activation and ibrutinib response in our novel preclinical disease models, determining the effect of the microenvironment on BTK dependency, and exploring mechanisms of ibrutinib resistance and combination therapies to overcome resistance. Our overall goal is to further understand the role of BTK in the PCNSL response to ibrutinib, so that we can take steps to augment the positive results we have seen in patients.

项目概要/摘要 原发性中枢神经系统淋巴瘤（PCNSL）是一种侵袭性疾病，仅出现在 中枢神经系统（CNS）。由于其发病率低且患者样本质量差， 建立 PCNSL 的临床前疾病模型非常具有挑战性。因此，大多数 我们目前所掌握的有关 PCNSL 生物学和发病机制的知识基于以下领域的测序研究： 小规模患者群体，特别是基因表达研究和突变分析。基于基因表达 研究表明，大多数 PCNSL 被归类为弥漫性大 B 细胞淋巴瘤 (DLBCL)，这是最常见的形式 非霍奇金淋巴瘤。在三种 DLBCL 亚型中，PCNSL 最类似于激活的 B 细胞样 (ABC) 亚型。基于 PCNSL 肿瘤的突变分析，PCNSL 在髓系细胞中存在复发性突变 分化初级反应基因 88 (MYD88) (70%) 和分化簇 79B (CD79B) (40%)。 MYD88 是与 Toll 样受体 (TLR) 相关的衔接蛋白，而 CD79B 是 Toll 样受体 (TLR) 所需的分子 B 细胞受体 (BCR) 信号传导。 MYD88 和 CD79B 突变也存在于 ABC DLBCL 中，但并非如此 与 PCNSL 中的频率相同。这些突变与核因子激活增加有关 PCNSL 中活化 B 细胞 (NF-κB) 的 kappa 轻链增强子。已有多种靶向治疗 开发用于抑制该途径，一个例子（同类中的第一个）是依鲁替尼，一种布鲁顿酪氨酸激酶 （BTK）抑制剂。 BTK是BCR和TLR下游的中央信号节点。依鲁替尼 (ibrutinib) 抑制 BTK 最近已被证实 FDA 批准用于治疗多种 B 细胞恶性肿瘤。我们在纪念斯隆管理学院进行的 I/II 期临床试验 凯特林癌症中心对复发或难治性中枢神经系统淋巴瘤的研究显示，75% 的患者对 依鲁替尼。虽然这看起来可能只是 B 细胞谱系对 BTK 的成瘾，但我们认为这不太可能 因为某些 B 细胞恶性肿瘤实际上对依鲁替尼没有反应。此外，在研究患者中 对依鲁替尼有反应，一些人的 MYD88 和/或 CD79B 发生突变，而另一些人则没有，这表明 MYD88/CD79B 突变状态不足以解释依鲁替尼的反应。因此我们假设 PCNSL 对 BTK 具有整体依赖性，这并不是由于 B 细胞谱系成瘾所致。在提案中，我们的目标是 通过评估 BTK 激活和 PCNSL 之间的关系来了解 PCNSL 的 BTK 依赖性 依鲁替尼在我们的新型临床前疾病模型中的反应，确定微环境对 BTK依赖，探索依鲁替尼耐药机制和联合疗法克服 反抗。我们的总体目标是进一步了解 BTK 在 PCNSL 对依鲁替尼反应中的作用，以便 我们可以采取措施来增强我们在患者身上看到的积极结果。