Lymphoid Experimental Therapeutics Platform to Study Cooperative Signaling inHuman Lymphomas

研究人类淋巴瘤协同信号转导的淋巴实验治疗平台

• 批准号: 10206067
• 负责人: Ankur Singh
• 金额: $ 47.36万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10206067
• 关键词: Agammaglobulinaemia tyrosine kinase; Agonist; B-Cell Activation; B-Cell Antigen Receptor; B-Cell Lymphomas; B-Lymphocytes; Biocompatible Materials; Biological; Bypass; Cells; Chronic; Clinical; Clinical Trials; Complex; Correlative Study; Data; Dependence; Development; Dose; Drug Exposure; Epigenetic Process; Extracellular Matrix; Extranodal; Feedback; Genetically Engineered Mouse; Growth; Heterogeneity; Human; Hydrogels; Hyperactivity; Immune; In Vitro; Integrins; Investigational Therapies; Ligands; Link; Liquid substance; Lymphatic; Lymphoid; Lymphoid Tissue; Lymphoma; Malignant - descriptor; Measures; Mediating; Mediator of activation protein; Microfluidics; Molecular; Morphology; Mucosa- associated lymphoid tissue lymphoma translocation protein-1; Mus; Mutate; Mutation; Organoids; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Protein translocation; Proteins; Publishing; Receptor Activation; Receptor Signaling; Regulation; Relapse; Reporting; Research; Research Project Grants; Resistance; Role; Sampling; Scheme; Signal Pathway; Signal Transduction; Somatic Mutation; Source; Structure of germinal center of lymph node; Technology; Therapeutic; Time; Tissue Model; Tissues; Titrations; Toll-Like Receptor Pathway; Toll-like receptors; Translations; Treatment Efficacy; Treatment Protocols; Work; Xenograft procedure; base; cancer cell; clinical investigation; combinatorial; cooperative study; defined contribution; design; flexibility; fluid flow; in vivo; in vivo Model; inhibitor/antagonist; innovation; kinetic model; large cell Diffuse non-Hodgkin' s lymphoma; lymph nodes; lymphoid neoplasm; neoplastic cell; patient subsets; personalized medicine; potential biomarker; pre-clinical; protein activation; response; small molecule inhibitor; targeted treatment; therapeutic target; tumor; tumor microenvironment

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.

弥漫性B细胞淋巴瘤DLBCL的活化B细胞（ABC）亚型的患者中约有40％ 当前疗法复发或不健康。 ABC-DLBCL具有抵抗力的机制 当前的疗法尚不清楚，但可能与其中的特定体细胞突变有关 肿瘤与淋巴肿瘤微环境提供的复杂生长信号协同 （ly-tme）。许多Hallmark ABC-DLBCL突变导致B细胞受体（BCR）的组成型激活 和这些恶性免疫细胞中的接收器（TLR）途径。因此，这些途径正在出现 作为治疗ABC-DLBCL的治疗靶标的来源。但是，迄今为止，现有的BCR途径 在有限的患者子集中，诸如靶向布鲁顿酪氨酸激酶（BTK）的抑制剂（BTK）和 仅在短时间内（几个月），其原因是未知的。响应的实质差异 ABC-DLBCL患者之间的速率和响应持续时间反映了对BCR和TLR的可变依赖性 通过LY-TME的信号传导和/或差分调节。因此，ly-tme对于ABC-DLBCL似乎至关重要 信号通路的构成作用。 ABC-DLBCL有多个合作和喂养，并且 促进肿瘤存活和个性化治疗的旁路信号通路将需要组合 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 众所周知，ABC-DLBCL中的途径以及有关靶向治疗的有效性的途径。 因此，该R01的目的是通过Ly-TME和 确定LY-TME在ABC-DLBCL存活，信号传导和对途径抑制剂的反应中的作用 粘膜相关的淋巴组织淋巴瘤易位蛋白1（MALT1）paracaspase。通过集成 R01的结果，团队将确定LY-TME在BCR-MALT1和TLR信号中的作用 DLBCL并确定更精致的给药方案。该R01的机制将增加“预测性 MALT1抑制剂的功率”，并提供了对MALT1抑制剂抗性的机械线索，并且 发现组合治疗以克服抗药性。