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，近 70,000 人被诊断出非霍奇金淋巴瘤 (NHL) 每年美国人的 B 细胞受体信号在非霍奇金淋巴瘤（包括慢性霍奇金淋巴瘤）中被不当激活。 90% 的 CLL 肿瘤患者对淋巴细胞白血病 (CLL) 和套细胞淋巴瘤 (MCL) 有反应。 使用布鲁顿酪氨酸激酶 (BTK) 抑制剂依鲁替尼治疗，但在超过 60% 的病例中， 治疗最终会失败，一旦失败，患者就会对其他靶向策略和肿瘤产生耐药性。 我们的初步数据显示，长期依鲁替尼的治疗变得迅速，导致生存进展时间缩短。 淋巴瘤细胞系和原发性肿瘤的治疗导致选择可重复表现出的细胞： 活性氧产生增加、磷酸酶活性降低以及 DNA 上调 基于这些数据，我们勇敢地治疗了一部分 CLL 和 MCL 肿瘤。 与依鲁替尼一起使用会导致可重复的代谢变化，从而导致活性氧增加 物种，这一过程可能先于 BTK 产生抗性突变。 依鲁替尼驱动的活性氧的增加负责氧化和抑制 酪氨酸磷酸酶和鸟嘌呤氧化，导致 DNA 损伤增加。 相信这些由依鲁替尼驱动的改变也可以被靶向，并且这样做可能会导致 为了检验这些假设，我们将 (1) 重新获得疾病控制或预防获得性耐药性。 开发敏感的基于蛋白质的检测来监测依鲁替尼耐药的分子指标，包括 活性氧的改变 (2) 研究调节依鲁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 依鲁替尼在从患者体内纵向分离的原发性 CLL 和 MCL 肿瘤细胞中引发的变化。 我们追求：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 产生对依鲁替尼的获得性耐药性；b) 直接靶向该信号传导程序将导致 最终，我们建议开发能够改善反应的组合或序贯疗法。 该监测信号程序将确定针对特定患者的额外疗法 如果与依鲁替尼联合或顺序给药，可能会成功。