Mechanisms mediating resistance to ibrutinib in Non-Hodgkin's lymphoma

非霍奇金淋巴瘤伊布替尼耐药的介导机制

• 批准号: 9237831
• 负责人: Richard Goff James
• 金额: $ 44.8万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9237831
• 关键词: Acute; Agammaglobulinaemia tyrosine kinase; American; Automobile Driving; B lymphoid malignancy; BCL2 gene; Biological Assay; Catalogs; Cell Line; Cells; Chronic Lymphocytic Leukemia; Clinical; DNA Damage; DNA Repair; DNA Repair Gene; DNA Repair Pathway; Data; Development; Diagnosis; Drug resistance; Enzymes; Exhibits; Failure; Growth; Guanine; Investigation; Lead; Length; Lymphoma; Mantle Cell Lymphoma; Mediating; Metabolic; Metabolism; Mitochondria; Molecular; Monitor; Mutation; Non-Hodgkin' s Lymphoma; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Population; Preparation; Primary Neoplasm; Process; Production; Progression-Free Survivals; Protein Tyrosine Phosphatase; Proteins; Proteome; Reactive Oxygen Species; Receptor Signaling; Receptors, Antigen, B-Cell; Refractory; Reproducibility; Resistance; SYK gene; Sampling; Signal Transduction; Testing; Therapeutic; Time; Up-Regulation; World Health Organization; base; combinatorial; disorder control; disorder prevention; drug efficacy; drug sensitivity; improved; inhibitor/antagonist; killings; neoplastic cell; oxidation; programs; prospective; response; small molecule; treatment response; tumor; tumor progression

According to the World Health Organization, Non-Hodgkin’s Lymphoma (NHL) is diagnosed in nearly 70,000 Americans per year. Signals from the B-cell receptor are inappropriately activated in NHL, including in Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL). 90% of CLL tumors patients respond to treatment with ibrutinib, an inhibitor of Bruton’s Tyrosine Kinase (BTK), however in >60% of those cases, the therapy eventually fails. Upon failure, patients are refractory to other targeting strategies and tumor progression becomes rapid, leading to short survival times. Our preliminary data show that long-term ibrutinib treatment of lymphoma cell lines and primary tumors leads to selection for cells that reproducibly exhibit: increased production of reactive oxygen species, decreased phosphatase activity, and up-regulation of DNA repair pathways. Based on this data, we hypothesize that treatment of a subset of CLL and MCL tumors with ibrutinib results in reproducible metabolic changes that lead to increased reactive oxygen species, a process that may precede resistance-conferring mutations in BTK. We hypothesize that ibrutinib-driven increases in reactive oxygen species are responsible for oxidation and inhibition of tyrosine phosphatases and for oxidation of guanine, leading to increased DNA damage. Finally, we believe that these ibrutinib-driven alterations can be also be targeted, and that doing so could result in regained disease control or prevention of acquired resistance. To test these hypotheses we will (1) develop sensitive protein-based assays to monitor molecular indicators of ibrutinib resistance including alterations in reactive oxygen species (2) investigate the impact of modulating ibrutinib-driven reactive oxygen species in CLL cell lines and tumor cells, and (3) comprehensively catalog cell signaling and drug sensitivity changes initiated by ibrutinib in primary CLL and MCL tumor cells isolated longitudinally from patients. We hypothesize that: a) by monitoring these changes we can help to predict which subjects are most likely to develop acquired resistance to ibrutinib; and b) direct targeting of this altered signaling program will lead to the development of combinatorial or sequential therapies enabling improved response. Ultimately, we propose that monitoring this altered signaling program will determine, for a given patient, which additional therapies are likely to be successful if given in combination or sequence with ibrutinib.

根据世界卫生组织的数据，非霍奇金淋巴瘤（NHL）在近70，000 美国人每年来自B细胞受体的信号在NHL中被不适当地激活，包括在慢性NHL中。 淋巴细胞白血病（CLL）和套细胞淋巴瘤（MCL）。90%的CLL肿瘤患者对 使用布鲁顿酪氨酸激酶（BTK）抑制剂伊曲替尼治疗，然而，在>60%的这些病例中， 治疗最终失败。一旦失败，患者对其他靶向策略和肿瘤治疗是难治的。 进展迅速，导致生存期缩短。我们的初步数据显示，长期服用伊鲁替尼 淋巴瘤细胞系和原发性肿瘤的治疗导致选择可再现地表现出以下特征的细胞： 活性氧的产生增加，磷酸酶活性降低，DNA表达上调 修复路径。基于这些数据，我们假设治疗CLL和MCL肿瘤的一个子集， 伊曲替尼导致可重现的代谢变化，导致活性氧增加 物种，一个过程，可能之前的耐药赋予突变的BTK。我们假设 伊替尼驱动的活性氧增加是氧化和抑制 酪氨酸磷酸酶和鸟嘌呤的氧化，导致DNA损伤增加。最后我们 我相信，这些伊替尼驱动的改变也可以有针对性，这样做可能会导致 恢复疾病控制或预防获得性抗性。为了验证这些假设，我们将（1） 开发敏感的基于蛋白质的检测方法，以监测伊曲替尼耐药的分子指标，包括 活性氧的改变（2）研究调节伊替尼驱动的活性氧的影响 CLL细胞系和肿瘤细胞中的物种，以及（3）全面分类细胞信号传导和药物敏感性 在从患者纵向分离的原发性CLL和MCL肿瘤细胞中由伊鲁替尼引发的变化。我们 假设：a）通过监测这些变化，我们可以帮助预测哪些受试者最有可能 产生对伊布替尼的获得性耐药性;和B）直接靶向这种改变的信号传导程序将导致 开发能够改善反应的组合或序贯疗法。最后，我们建议， 监测这种改变的信号程序将确定，对于给定的患者， 如果与伊鲁替尼联合或顺序给药，可能会成功。