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

项目总结/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。 中枢神经系统（CNS）。由于其发病率低和患者样本质量差， 建立PCNSL的临床前疾病模型一直是一个挑战。因此，大多数 我们目前关于PCNSL生物学和发病机制的知识是基于以下方面的测序研究： 小型患者队列，特别是基因表达研究和突变分析。基于基因表达式 在研究中，大多数PCNSL被归类为弥漫性大B细胞淋巴瘤（DLBCL），这是PCNSL的最常见形式。 非霍奇金淋巴瘤。在三种DLBCL亚型中，PCNSL最类似于活化的B细胞样（ABC） 亚型基于PCNSL肿瘤的突变谱，PCNSL在骨髓中具有复发性突变， 分化初级反应基因88（MYD 88）（70%）和分化簇79 B（CD 79 B）（40%）。 MYD 88是与Toll样受体（TLR）相关的衔接蛋白，而CD 79 B是与Toll样受体（TLR）相关的分子。 B细胞受体（BCR）信号传导。MYD 88和CD 79 B突变也在ABC DLBCL中发现，但不与DLBCL相关。 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κ轻链增强子。几种靶向治疗已经 已经开发了一种抑制这种途径的药物，其中一个例子（同类药物中的第一个）是伊布替尼，一种布鲁顿酪氨酸激酶 (BTK)抑制剂. BTK是BCR和TLR下游的中央信令节点。最近， FDA批准用于治疗几种B细胞恶性肿瘤。我们在Memorial Sloan进行的I/II期临床试验 Kettering癌症中心在复发性或难治性CNS淋巴瘤中的研究显示，75%的患者对 伊替尼。虽然这似乎只是B细胞谱系对BTK的成瘾，但我们认为这不太可能 因为一些B细胞恶性肿瘤实际上对伊布替尼没有反应。此外，在研究患者中， 在对伊曲替尼有反应的患者中，一些人在MYD 88和/或CD 79 B中有突变，而另一些人则没有，这表明 MYD 88/CD 79 B突变状态不足以解释伊曲替尼的反应。因此，我们假设， PCNSL对BTK具有总体依赖性，这不是由于B细胞谱系成瘾。在提案中，我们旨在 通过评估BTK激活与PCNSL的关系，了解PCNSL的BTK依赖性。 在我们的新型临床前疾病模型中，确定微环境对 BTK依赖性，并探索伊鲁替尼耐药的机制和联合治疗，以克服 阻力我们的总体目标是进一步了解BTK在PCNSL对伊曲替尼反应中的作用， 我们可以采取措施来扩大我们在病人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.