Overcoming ibrutinib resistance in mantle cell lymphoma
克服套细胞淋巴瘤中的依鲁替尼耐药性
基本信息
- 批准号:10559495
- 负责人:
- 金额:$ 44.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAffectAgammaglobulinaemia tyrosine kinaseAgeAggressive Clinical CourseApoptosisB-Cell ActivationB-Cell Antigen ReceptorB-LymphocytesBCL2 geneBIRC3 geneBloodBone MarrowCell Cycle ProteinsCell LineCell physiologyCellsCessation of lifeChronicChronic Lymphocytic LeukemiaClinical TrialsCyclin D1DataDevelopmentDiagnosisDiseaseEnzyme InhibitionEnzymesEvaluationExhibitsFailureFamilyFutureGenesGeneticGenetic Complementation TestGenetic TranscriptionHomingImmuneImmuno-ChemotherapyImmunosuppressionIn VitroInvestigationLigaseLymphoid CellLymphomaLymphoma cellMalignant - descriptorMantle Cell LymphomaMediatingMusMutationNeoplasmsNewly DiagnosedNon-Hodgkin&aposs LymphomaNuclearOutcomePathogenesisPathogenicityPathway interactionsPatientsPatternPhase I Clinical TrialsPhenotypePhospholipasePhosphotransferasesPlayPrognosisProgressive DiseaseProliferatingProspective StudiesProtein FamilyRELA geneReceptor SignalingRecurrenceRefractoryRegimenRegulationRegulatory T-LymphocyteRelapseResistanceResistance developmentRoleSamplingSignal PathwaySignal TransductionStromal NeoplasmSystemT-LymphocyteTRAF2 geneTestingTherapeuticTherapeutic InterventionTissuesUbiquitinUbiquitin-Activating EnzymesUp-RegulationXenograft Modelchemokinechemotherapyclinical translationhigh-throughput drug screeningimmunoregulationin vivoinhibitorlymph node microenvironmentlymph nodesmouse modelmulticatalytic endopeptidase complexneoplasticneoplastic cellnovel strategiespatient derived xenograft modelpharmacologicphase II trialpre-clinicalprospectiveresponsesingle-cell RNA sequencingsynergismtherapeutic targettherapeutically effectivetherapy resistanttumortumor microenvironment
项目摘要
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Alexey V. Danilov其他文献
Pharmacodynamic Analysis of Mcl-1 and RNA Pol IIsupSer2/sup Phosphorylation in Blasts from Patients with Relapsed or Refractory Acute Myeloid Leukemia Treated on a Phase 1 Study of Venetoclax Plus Voruciclib
维奈托克联合沃罗诺克拉治疗复发性或难治性急性髓系白血病患者的原始细胞中 Mcl-1 和 RNA 聚合酶 II 丝氨酸 2 磷酸化的药效学分析
- DOI:
10.1182/blood-2024-203689 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:23.100
- 作者:
Nathalie Javidi-Sharifi;Jeremy Zhang;Sandra Wiley;Richard G Ghalie;Alexey V. Danilov;Matthew S. Davids - 通讯作者:
Matthew S. Davids
Glofitamab stimulates immune cell infiltration of CNS tumors and induces clinical responses in secondary CNS lymphoma
格罗菲妥单抗可刺激中枢神经系统肿瘤的免疫细胞浸润,并在继发性中枢神经系统淋巴瘤中诱导临床缓解 。
- DOI:
10.1182/blood.2024024168 - 发表时间:
2024-07-25 - 期刊:
- 影响因子:23.100
- 作者:
James K. Godfrey;Lei Gao;Geoffrey Shouse;Joo Y. Song;Stacy Pak;Brian Lee;Bihong T. Chen;Avyakta Kallam;John H. Baird;Guido Marcucci;Lucy Ghoda;Stephanie Vauleon;Alexey V. Danilov;Alex F. Herrera;Larry W. Kwak;Lihua E. Budde - 通讯作者:
Lihua E. Budde
Nx-2127 and Nx-5948, Two Clinical Stage Cereblon-Recruiting BTK Degraders, Facilitate T Cell Functionality in Chronic Lymphocytic Leukemia
- DOI:
10.1182/blood-2024-204184 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:
- 作者:
Tiana Huynh;Sonia Rodriguez-Rodriguez;Carly Roleder;Sarah Whelan;May Tan;Ernestine Lee;Paul Munson;Alexey V. Danilov - 通讯作者:
Alexey V. Danilov
Impact of Novel Therapies (NTs) on Real-World (RW) Clinical Outcomes of Patients (pts) with Relapsed/Refractory (RR) Mantle-Cell Lymphoma (MCL) By Race/Ethnicity and <em>TP53</em> Mutation Status
- DOI:
10.1182/blood-2024-204269 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:
- 作者:
Tycel J. Phillips;Alexey V. Danilov;Jia Ruan;Krish Patel;Anita Kumar;Yucai Wang;Gregory A. Maglinte;Erlene Seymour;Manali Kamdar - 通讯作者:
Manali Kamdar
High-Risk Mantle Cell Lymphoma in the Era of Novel Agents
- DOI:
10.1007/s11899-021-00605-9 - 发表时间:
2021-01-28 - 期刊:
- 影响因子:3.300
- 作者:
Edward Nabrinsky;Alexey V. Danilov;Paul B. Koller - 通讯作者:
Paul B. Koller
Alexey V. Danilov的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Alexey V. Danilov', 18)}}的其他基金
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:
10320471 - 财政年份:2021
- 资助金额:
$ 44.13万 - 项目类别:
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 44.13万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 44.13万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 44.13万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 44.13万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 44.13万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 44.13万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 44.13万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 44.13万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 44.13万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 44.13万 - 项目类别:
Studentship