Lymphoid Experimental Therapeutics Platform to Study Cooperative Signaling inHuman Lymphomas

大约40%的弥漫性大B细胞淋巴瘤DLBCL的活化B细胞（ABC）亚型患者 复发或不能用目前的疗法治愈。ABC-DLBCL耐药的机制 目前的治疗方法是未知的，但可能与这些疾病中特定的体细胞突变谱有关。 肿瘤，这与淋巴肿瘤微环境提供的复杂生长信号一致 （Ly-TME）。许多标志性ABC-DLBCL突变导致B细胞受体（BCR）的组成性激活 和Toll样受体（TLR）途径。因此，这些途径正在出现 作为治疗ABC-DLBCL的治疗靶点来源。然而，到目前为止，现有的BCR途径 诸如靶向布鲁顿酪氨酸激酶（BTK）的抑制剂在有限的患者亚群中是有活性的， 仅在短时间内（几个月），其原因不明。反应的实质性差异 ABC-DLBCL患者之间的缓解率和缓解持续时间反映了对BCR和TLR的可变依赖性 信号传导和/或Ly-TME的差异调节。因此，Ly-TME似乎对于ABC-DLBCL至关重要， 尽管信号通路的组成性作用。ABC-DLBCL具有多重协作和反馈， 促进肿瘤存活的旁路信号通路和个性化治疗需要结合 治疗，以充分抑制这些网络。不幸的是，Ly-TME对这些信号的影响 对ABC-DLBCL中的信号通路以及因此对靶向治疗剂的功效的影响知之甚少。 因此，本R 01的目的是开发一种使用Ly-TME的实验性治疗技术， 确定Ly-TME对ABC-DLBCL存活、信号传导和对ABC-DLBCL通路抑制剂的反应的作用。 粘膜相关淋巴组织淋巴瘤易位蛋白1（MALT 1）半胱天冬酶。通过整合 R 01的结果，研究小组将确定Ly-TME在ABC中BCR-MALT 1和TLR信号传导中的作用。 DLBCL，并确定更精确的给药方案。该R 01的机制将增加“预测性 MALT 1抑制剂的“功率”，并提供对MALT 1抑制剂耐药性的机制线索，以及 发现联合疗法来克服耐药性。

Approximately 40% of patients with activated B cell (ABC) subtype of diffuse large B cell lymphoma DLBCL relapse or are not curable with current therapies. The mechanism through which ABC-DLBCLs are resistant to current therapies are unknown but may be linked to the particular spectrum of somatic mutations in these tumors, which are in concert with complex growth signals provided by the lymphoid tumor microenvironment (Ly-TME). Many of the hallmark ABC-DLBCL mutations result in constitutive activation of B cell receptor (BCR) and Toll like receptor (TLR) pathways in these malignant immune cells. Hence these pathways are emerging as a source of therapeutic targets for the treatment of ABC-DLBCLs. However, to date, existing BCR pathway inhibitors such as those targeting Bruton’s tyrosine kinase (BTK) are active in a limited subset of patients and only for a short duration (few months), causes of which are unknown. The substantial differences in response rates and response duration between ABC-DLBCL patients reflect the variable dependencies on BCR and TLR signaling and/or differential regulation by the Ly-TME. Therefore, Ly-TME seems essential for ABC-DLBCLs in spite of constitutive action of signaling pathways. ABC-DLBCLs have multiple cooperative and feed-back, and bypass signaling pathways that promote tumor survival and personalized therapy will require combination therapeutics to adequately suppress these networks. Unfortunately, the impact of Ly-TME on these signaling pathways in ABC-DLBCLs and, consequently, on the efficacy of targeted therapeutics are poorly understood. Therefore, the objective of this R01 is to develop an experimental therapeutics technology with Ly-TME and determine the role of Ly-TME on ABC-DLBCL survival, signaling, and response to pathway inhibitors of the Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) paracaspase. By integrating the results of R01, the team will determine the role of Ly-TME in BCR-MALT1 and TLR signaling in ABC- DLBCL and determine a more refined dosing scheme. Mechanisms from this R01 will increase “predictive power” of MALT1 inhibitors, and provide mechanistic clues towards resistance to MALT1 inhibitors, and discover combinatorial therapy to overcome resistance.