Lymphoid Experimental Therapeutics Platform to Study Cooperative Signaling inHuman Lymphomas

约40%的弥漫性大B细胞淋巴瘤患者具有激活的B细胞(ABC)亚型 复发或不能用目前的治疗方法治愈。ABC-DLBCL的抗性机制 目前的治疗方法尚不清楚，但可能与这些细胞中特定的体细胞突变谱有关 肿瘤，与淋巴样肿瘤微环境提供的复杂生长信号相一致 (Ly-TME)。许多标志性的ABC-DLBCL突变导致B细胞受体(BCR)的结构性激活 这些恶性免疫细胞中的Toll样受体(TLR)通路。因此，这些路径正在出现 作为ABC-DLBCL治疗靶点的来源。然而，到目前为止，现有的BCR途径 针对Bruton‘s酪氨酸激酶(BTK)的抑制剂在有限的患者亚群中有效， 只持续很短的时间(几个月)，原因不明。在回应方面的重大差异 ABC-DLBCL患者的发生率和反应持续时间反映了BCR和TLR的不同依赖关系 Ly-TME的信令和/或差分调节。因此，Ly-TME对于ABC-DLBCL来说似乎是必不可少的 尽管有信号通路的本构作用。ABC-DLBCL具有多个协作性和反馈性 提高肿瘤存活率的旁路信号通路和个性化治疗将需要结合 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 ABC-DLBCL中的通路以及靶向治疗的疗效因此知之甚少。 因此，R01的目标是开发一种使用Ly-TME和 确定Ly-TME在ABC-DLBCL存活、信号转导和对途径抑制剂的反应中的作用 粘膜相关淋巴组织淋巴瘤转位蛋白1(MALT1)副天冬氨酸酶。通过集成 R01的结果，该团队将确定Ly-TME在ABC-BCR-MALT1和TLR信号转导中的作用。 DLBCL，并确定更精细的剂量方案。此R01中的机制将增加“预测性” MALT1抑制剂的“威力”，并为MALT1抑制剂的耐药性提供机制线索，以及 发现克服耐药性的组合疗法。

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.