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

项目摘要/摘要 原发性中枢神经系统淋巴瘤(PCNSL)是一种侵袭性疾病，仅表现于 中枢神经系统(CNS)。由于其发病率低和患者样本质量差，它已经 建立PCNSL的临床前疾病模型非常具有挑战性。因此，大多数人 我们目前对PCNSL生物学和发病机制的了解是基于 小患者队列，特别是基因表达研究和突变图谱。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)，是 非霍奇金淋巴瘤。在DLBCL的三种亚型中，PCNSL与激活的B细胞样细胞(ABC)最为相似 子类型。根据PCNSL肿瘤的突变谱，PCNSL在髓系中有反复突变 分化主反应基因88(MYD88)(70%)和分化簇79B(CD79B)(40%)。 MyD88是一种与Toll样受体(TLR)相关的接头蛋白，而CD79B是与Toll样受体(TLR)相关的分子 B细胞受体(BCR)信号转导。在ABC DLBCL中也发现了MyD88和CD79B突变，但没有发现 与PCNSL相同的频率。这些突变与核因子的激活增加有关。 活化B细胞轻链增强子(NF-κB)在PCNSL中的表达已经有几种靶向治疗方法 被开发来抑制这一途径，一个例子(班上第一个)是伊布鲁替尼，一种布鲁顿酪氨酸激酶 (BTK)抑制剂。 BTK是BCR和TLR下游的中心信令节点。最近，伊布鲁替尼对BTK的抑制作用 FDA批准用于治疗几种B细胞恶性肿瘤。我们在斯隆纪念医院的I/II期临床试验 凯特琳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 伊布鲁替尼。尽管这可能看起来只是B细胞对BTK的上瘾，但我们认为这不太可能 因为一些B细胞肿瘤实际上对伊布鲁替尼没有反应。此外，在研究的患者中， 对ibrutinib的反应，一些人在MYD88和/或CD79B上有突变，而另一些人没有，这表明 MyD88/CD79B突变状态不足以解释伊布鲁替尼的反应。因此，我们假设 PCNSL对BTK有总体依赖，这不是由于B细胞血统成瘾。在提案中，我们的目标是 通过评估BTK激活与PCNSL的关系来了解PCNSL对BTK的依赖 伊布鲁替尼在我们新的临床前疾病模型中的反应，确定微环境对 BTK依赖，并探索伊布鲁替尼耐药的机制和联合治疗以克服 抵抗。我们的总体目标是进一步了解BTK在PCNSL对ibrutinib的反应中的作用，以便 我们可以采取措施，扩大我们在患者身上看到的积极结果。

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.