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 伊布鲁替尼，布鲁顿酪氨酸激酶(BTK)和类似的B细胞受体(BCR)抑制剂的共价抑制剂- 相关的激酶正在改变B细胞肿瘤的治疗格局。然而，中国的发展 接受这些药物治疗的患者的耐药性与迅速进展的疾病和死亡有关。 Btk及其下游靶基因磷脂酶Cγ2的突变与伊布鲁替尼的耐药性有关 慢性淋巴细胞白血病(CLL)。而这种突变是在套细胞淋巴瘤的一个亚群中发现的 (MCL)患者，他们并不能解释ibrutinib耐药的所有模式。最近的研究表明， 核因子-κB(核因子-κB)作为MCL耐药的潜在关键成分。黄连的致病作用 核因子κB是由a)激活淋巴结内的核因子κB信号通路支持的 微环境；b)TRAF2，BIRC3和TRAF2，BIRC3，TRAF2，BIRC3和TRAF2，BIRC3，TRAF2，BIRC3，TRAF2，BIRC3和κ C)在对伊布鲁替尼耐药的原发微淋巴细胞系样本中，影响核因子κB信号转导的基因突变。因此， 肿瘤内在和微环境驱动的NFκB激活可能是伊布鲁替尼的重要组成部分 失败。然而，在这一背景下，还没有前瞻性地研究NFκB的作用。我们假设 在对伊布鲁替尼表现出耐药的患者中，NFκB及其转录靶点上调。在目标1下， 我们将进行一项前瞻性研究，以确定伊布鲁替尼中核因子κB激活的功能意义 MCL中的抗性。我们将全面评估从骨获得的原代MCL细胞中的NFκB信号 伊布鲁替尼开始治疗前、治疗时和复发时的骨髓和/或淋巴转移。鉴于新兴的 核因子κB在微淋巴细胞性淋巴瘤中的重要性，最佳的治疗方法应包括靶向核因子κB的激活。在……里面 评价作为治疗靶点的核因子κB通路，我们发现它可以通过阻断 泛素-蛋白酶体系统(UPS)的上游调节因子。我们的数据表明，核因子κB的活性可能是 通过靶向肿瘤B细胞中的NEDD8激活酶(NAE；一种泛素样修饰物)而被阻断，结果 在细胞凋亡中。我们推测，通过阻断NAE对核因子κB的治疗干扰将克服 MCL对伊布鲁替尼耐药。因此，AIM 2将评估伊布鲁替尼中E1连接酶NAE的治疗靶向性。 抗性MCL。我们将阐明抑制NAE在MCL中对NFκB信号转导、细胞凋亡的作用 体外和小鼠MCL异种移植模型中的伊布鲁替尼耐药细胞系和原代耐药细胞。最后，《目标3》将 评估NAE抑制介导的肿瘤B细胞和T细胞中NFκB的去调节作用 在临床试验中接受培诺地塞米松和伊布鲁替尼治疗的患者。我们的研究将测试小说 通过核因子κB失活克服伊布鲁替尼耐药性的方法，从而显著影响MCL 治疗学。