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，非霍奇金的淋巴瘤（NHL）被诊断出近70,000 美国人每年。来自B细胞受体的信号在NHL中不当激活，包括慢性 淋巴细胞性白血病（CLL）和地幔细胞淋巴瘤（MCL）。 90％的CLL肿瘤患者对 ibrutinib是布鲁顿的酪氨酸激酶（BTK）的抑制剂，但是在这些情况中，有60％的情况 治疗最终失败。失败后，患者对其他靶向策略和肿瘤感到难治 进展变得迅速，导致生存时间较短。我们的初步数据表明长期ibrutinib 淋巴瘤细胞系和原发性肿瘤的治疗导致选择可重复暴露的细胞： 活性氧的产生增加，磷酸酶活性降低和DNA上调 维修途径。基于这些数据，我们假设对CLL和MCL肿瘤的子集进行治疗 依鲁替尼会导致可再现的代谢变化，从而导致活性氧增加 物种，该过程可能是BTK中抗性的突变。我们假设这一点 ibrutinib驱动的活性氧的增加是氧化和抑制 酪氨酸磷酸酶和鸟嘌呤的氧化，导致DNA损伤增加。最后，我们 认为这些依鲁替尼驱动的改变也可以是针对的，并且这样做可能会导致 持续的疾病控制或预防获得的抗药性。为了检验这些假设，我们将（1） 开发基于敏感蛋白质的测定法，以监测依鲁鲁替尼抗性的分子指标 活性氧的改变（2）研究了调节ibrutinib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）全面分类细胞信号和药物敏感性 Ibrutinib在原发性CLL和MCL肿瘤细胞中从患者纵向分离的变化。我们 假设：a）通过监视这些更改，我们可以帮助预测哪些受试者最有可能 产生对伊布鲁替尼的抗药性； b）直接针对此更改的信号计划将导致 合并或顺序疗法的发展，可以改善反应。最终，我们建议 监视此更改的信号计划将确定给定患者的其他疗法 如果与依鲁替尼结合或序列，可能会成功。