Overcoming ibrutinib resistance in mantle cell lymphoma

克服套细胞淋巴瘤中的依鲁替尼耐药性

• 批准号: 10559495
• 负责人: Alexey V. Danilov
• 金额: $ 44.13万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559495
• 关键词: Address; Affect; Agammaglobulinaemia tyrosine kinase; Age; Aggressive Clinical Course; Apoptosis; B-Cell Activation; B-Cell Antigen Receptor; B-Lymphocytes; BCL2 gene; BIRC3 gene; Blood; Bone Marrow; Cell Cycle Proteins; Cell Line; Cell physiology; Cells; Cessation of life; Chronic; Chronic Lymphocytic Leukemia; Clinical Trials; Cyclin D1; Data; Development; Diagnosis; Disease; Enzyme Inhibition; Enzymes; Evaluation; Exhibits; Failure; Family; Future; Genes; Genetic; Genetic Complementation Test; Genetic Transcription; Homing; Immune; Immuno-Chemotherapy; Immunosuppression; In Vitro; Investigation; Ligase; Lymphoid Cell; Lymphoma; Lymphoma cell; Malignant - descriptor; Mantle Cell Lymphoma; Mediating; Mus; Mutation; Neoplasms; Newly Diagnosed; Non-Hodgkin' s Lymphoma; Nuclear; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pattern; Phase I Clinical Trials; Phenotype; Phospholipase; Phosphotransferases; Play; Prognosis; Progressive Disease; Proliferating; Prospective Studies; Protein Family; RELA gene; Receptor Signaling; Recurrence; Refractory; Regimen; Regulation; Regulatory T-Lymphocyte; Relapse; Resistance; Resistance development; Role; Sampling; Signal Pathway; Signal Transduction; Stromal Neoplasm; System; T-Lymphocyte; TRAF2 gene; Testing; Therapeutic; Therapeutic Intervention; Tissues; Ubiquitin; Ubiquitin-Activating Enzymes; Up-Regulation; Xenograft Model; chemokine; chemotherapy; clinical translation; high-throughput drug screening; immunoregulation; in vivo; inhibitor; lymph node microenvironment; lymph nodes; mouse model; multicatalytic endopeptidase complex; neoplastic; neoplastic cell; novel strategies; patient derived xenograft model; pharmacologic; phase II trial; pre-clinical; prospective; response; single-cell RNA sequencing; synergism; therapeutic target; therapeutically effective; therapy resistant; tumor; tumor microenvironment

Project Abstract Ibrutinib, a covalent inhibitor of Bruton tyrosine kinase (BTK) and similar inhibitors of B-cell receptor (BCR)- associated kinases are shifting the therapeutic landscape in B-cell neoplasia. However, the development of resistance in patients treated with these agents is associated with rapidly progressive disease and death. Mutations in BTK and its downstream target phospholipase Cγ2 have been implicated in resistance to ibrutinib in chronic lymphocytic leukemia (CLL). While such mutations are found in a subset of mantle cell lymphoma (MCL) patients, they do not account for all patterns of ibrutinib resistance. Recent studies have implicated nuclear factor-κB (NFκB) as a potential critical component of resistance in MCL. The pathogenic contribution of NFκB is supported by identification of a) activation of NFκB signaling pathways within the lymph node microenvironment; b) constitutive NFκB activity resulting from recurrent mutations in TRAF2, BIRC3 and RELA; and c) mutations in genes affecting NFκB signaling in primary ibrutinib-refractory MCL samples. Thus, tumor-intrinsic and microenvironment-driven NFκB activation may underlie a significant fraction of ibrutinib failures. However, the role of NFκB has not been studied prospectively in this setting. We hypothesize that NFκB and its transcriptional targets are upregulated in patients who exhibit resistance to ibrutinib. Under Aim 1, we will conduct a prospective study to determine functional significance of NFκB activation in ibrutinib resistance in MCL. We will comprehensively evaluate NFκB signaling in primary MCL cells obtained from bone marrow and/or lymph nodes prior to the start of ibrutinib, on therapy and at relapse. Given the emerging importance of NFκB in MCL, an optimal therapeutic approach would incorporate targeting NFκB activation. In evaluating the NFκB pathway as a therapeutic target, we discovered that it can be neutralized via blockade of upstream regulators in the ubiquitin-proteasome system (UPS). Our data indicate that NFκB activity may be blocked by targeting NEDD8-activating enzyme (NAE; a ubiquitin-like modifier) in neoplastic B-cells, resulting in cell apoptosis. We hypothesize that therapeutic disruption of NFκB by blocking the NAE will overcome ibrutinib resistance in MCL. Thus, Aim 2 will evaluate therapeutic targeting of the E1 ligase, NAE, in ibrutinib- resistant MCL. We will elucidate functional effects of inhibiting NAE on NFκB signaling, cell apoptosis in MCL cell lines and primary ibrutinib-resistant cells in vitro and in a murine MCL xenograft model. Finally, Aim 3 will assess the NAE inhibition-mediated deregulation of NFκB in neoplastic B cells and T cells obtained from patients who receive treatment with pevonedistat and ibrutinib on a clinical trial. Our study will test novel approaches to overcome ibrutinib resistance through NFκB inactivation, and thus significantly impact MCL therapeutics.

项目摘要 Ibrutinib，Bruton酪氨酸激酶（BTK）的共价抑制剂和B细胞受体（BCR）的类似抑制剂 - 相关的激酶正在转移B细胞肿瘤中的治疗景观。但是，发展 这些药物治疗的患者的耐药性与快速进行性疾病和死亡有关。 BTK及其下游靶磷脂酶Cγ2的突变已隐含于对Ibrutinib的抗性 在慢性淋巴细胞性白血病（CLL）中。尽管在地幔细胞淋巴瘤的一部分中发现了这种突变 （MCL）患者，他们没有考虑所有依鲁鲁替尼抗性的模式。最近的研究已经实施 核因子-κB（NFκB）是MCL耐药性的潜在关键成分。致病性贡献 通过识别a）淋巴结内NFκB信号通路的激活来支持NFκB 微环境； b）一致性NFκB活性由TRAF2，BIRC3和 rela; c）在原发性ibrutinib-侵产性MCL样品中影响NFκB信号传导的基因突变。那， 肿瘤内和微环境驱动的NFκB激活可能是ibrutinib的大部分 失败。但是，在这种情况下，NFκB的作用尚未研究。我们假设这一点 NFκB及其转录靶标在暴露于依鲁替尼的患者中进行了更新。在AIM 1下， 我们将进行一项前瞻性研究，以确定ibrutinib中NFκB激活的功能显着性 MCL的阻力。我们将全面评估从骨骼获得的原代MCL细胞中的NFκB信号传导 ibrutinib开始之前，治疗和退休时，骨髓和/或淋巴结。考虑到新兴 NFκB在MCL中的重要性，最佳的治疗方法将结合靶向NFκB激活。在 将NFκB途径评估为治疗靶标，我们发现它可以通过封锁而中和 泛素蛋白酶体系统（UPS）中的上游调节器。我们的数据表明NFκB活性可能是 通过靶向NEDD8激活酶（NAE；一种泛素样修饰剂）在肿瘤B细胞中阻塞，从而阻止 在细胞凋亡中。我们假设通过阻止NAE来克服NFκB的治疗性破坏 MCl中的ibrutinib抗性。这是AIM 2将评估E1连接酶NAE的治疗靶向，在Ibrutinib- 抗性MCL。我们将阐明抑制NAE对NFκB信号传导，MCL细胞凋亡的功能作用 在体外和鼠MCL特征模型中，细胞系和原发性ibrutinib耐药细胞。最后，AIM 3将 评估NAE抑制介导的NFκB在肿瘤B细胞和从T细胞中获得的NFκB的失调 接受Pevonedistat和Ibrutinib接受治疗的患者在临床试验中接受治疗。我们的研究将测试小说 通过NFκB失活克服依鲁鲁替尼的方法，从而显着影响MCL 疗法。