Targeting c-Myc stability in c-Myc overexpressing large B-cell lymphoma
靶向 c-Myc 过表达大 B 细胞淋巴瘤中的 c-Myc 稳定性
基本信息
- 批准号:10342915
- 负责人:
- 金额:$ 60.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:AccountingAdaptor Signaling ProteinAddressB-Cell LymphomasB-LymphocytesBCL2 geneBCL6 geneCCND1 geneCRISPR screenCell DeathCell SurvivalCellsCellular MorphologyChromosomal translocationClinicalComplexDataDiffuseDiseaseDisease modelEventF Box DomainFRAP1 geneGeneticGenetic TranscriptionImmuno-ChemotherapyImmunohistochemistryImmunologicsIn VitroInstitutionInvestigationLeadLymphomaLymphoma cellMediatingMethodsMolecularOncogenicOncoproteinsOutcomePathway interactionsPatientsPatternPharmacological TreatmentPharmacologyPhase Ib TrialPlayPre-Clinical ModelPrognosisPromoter RegionsProtein OverexpressionProteinsProto-Oncogene Proteins c-mycPublishingRefractoryRelapseReportingRoleSafetySignal TransductionTestingTherapeuticTransducinWNT Signaling PathwayWorkbasebeta cateninc-myc Genesin vivoin vivo Modelinhibitorknock-downmulticatalytic endopeptidase complexnovelnovel strategiesnovel therapeutic interventionoverexpressionpotential biomarkerpredicting responseprogramsprotein expressionrecruitresistance mechanismresponsesmall moleculetargeted treatment
项目摘要
Project Summary
Double (DH) and triple-hit (TH) lymphomas (L) are rare high grade B-cell lymphomas with diffuse large B-cell
(DLBCL) morphology characterized by the co-occurrence of chromosomal translocations involving MYC,
BCL2, and/or BCL6. DLBCLs with dual c-Myc (>40% by immunohistochemistry, IHC) and BCL2 (>50% by IHC)
protein overexpression without translocation (double-expressor or DEL) are significantly more common than
DH/THL, accounting for 20% to 30% of DLBCL patients. Lymphoma with either DEL, DHL, or THL are here
collectively called c-Myc overexpressing LBCL and have a significantly worse prognosis compared to the c-
Myc-negative counterpart [3-year overall survival of ~30% versus 70%, respectively]. The poor clinical
outcome of this subset of lymphoma patients highlights the need for novel therapeutic strategies. Transducin
β-like protein 1 (TBL1X) was initially identified as a specific adaptor protein playing an essential role in
canonical Wnt signaling by recruiting β-catenin to the promoter region of Wnt targets such as MYC and
CCND1 to activate their transcription. Few published reports indicate that the Wnt/β-catenin signaling is
constitutively activated in DLBCL, which prompted our initial investigation in this disease. Preliminary data: Our
published work shows that, unlike normal B cells, DLBCL cells express abundant levels of TBL1. Genetic
deletion of TBL1 or pharmacologic treatment with tegavivint (Iterion), a first-in-class small molecule targeting
TBL1, induces significant DLBCL cell death in vitro and in vivo. While tegavivint was initially developed as an
inhibitor of the TBL1/β-catenin interaction, our data show that genetic deletion of TBL1 and treatment with
tegavivint reduce c-Myc protein expression in a post-transcriptional/β-catenin independent manner. We further
show that in DLBCL, TBL1 interacts with a Skp1/Cul1/F-Box (SCF) supercomplex, which controls the
proteasome-mediated degradation of critical pro-survival proteins such as c-Myc and components of mTOR
signaling such as Rheb. Collectively, these observations establish the rationale for targeting TBL1 as a novel
therapeutic strategy to promote c-Myc turnover and to disrupt the driver events coordinated by its activity in c-
Myc overexpressing LBCL. Project hypothesis: TBL1 serves as a critical modulator of c-Myc turnover and
represents a novel and attractive candidate for targeted therapy for patients with c-Myc overexpressing LBCL.
To test this hypothesis, we propose the following aims: Aim 1: Characterize the TBL1/c-Myc feedforward
circuit promoting c-Myc overexpressing LBCL cell survival. Aim 2: Initiate a Phase Ib trial with single agent
tegavivint in patients with relapsed/refractory cMyc overexpressing LBCL. Aim 3: Identify combination
strategies to maximize the therapeutic potential of tegavivint. At completion of this project, we will have a better
understanding of the TBL1-modulated mechanism through which c-Myc turnover is regulated, will have
developed a novel therapeutic strategy to treat this incurable disease, and will have begun to characterize
resistance mechanisms to tegavivint.
项目摘要
二次(DH)和三次(TH)淋巴瘤(L)是罕见的伴有弥漫性大B细胞的高度恶性B细胞淋巴瘤
(DLBCL)以涉及MYC的染色体易位共存为特征的形态学,
BCL2和/或BCL6。双c-Myc(免疫组织化学检测为40%)和bcl2(免疫组化检测为50%)的DLBCL
没有易位的蛋白质过度表达(双表达或DEL)明显比
占DLBCL患者的20%~30%。淋巴瘤伴Del、DHL或THL
统称为c-Myc过表达的LBCL,与c-Myc相比,预后明显更差
MYC阴性患者[3年总存活率分别为30%和70%]。可怜的临床医生
这一亚组淋巴瘤患者的结果突出了对新的治疗策略的需要。换能器
β样蛋白1(TbL1X)最初被认为是一种特异性的接头蛋白,在
通过将β-连环蛋白募集到WNT靶标的启动子区域,如MYC和
CCND1激活它们的转录。少数已发表的报告表明,Wnt/β-catenin信号是
在DLBCL中被结构性激活,这促使我们对这种疾病进行了初步的研究。初步数据:我们的
已发表的研究表明,与正常的B细胞不同,DLBCL细胞表达丰富的TBL1。遗传
TBL1的缺失或用一流的小分子靶向药物替加韦(Iterion)进行药物治疗
TBL1在体内外均可诱导DLBCL细胞显著死亡。而tegavivint最初是作为一种
抑制TbL1/β-连环蛋白的相互作用,我们的数据表明,TbL1的基因缺失和
替加韦以转录后/β-连环蛋白非依赖的方式减少c-Myc蛋白表达。我们进一步
证明在DLBCL中,TBL1与Skp1/Cul1/F-Box(SCF)超复合体相互作用,该超复合体控制着
蛋白酶体介导的c-Myc和mTOR组分等关键促生存蛋白的降解
信令,如RHEB。总而言之,这些观察结果奠定了将TBL1作为一部小说的理论基础
促进c-Myc周转和干扰由其在c-Myc中的活动协调的驱动事件的治疗策略
MYC过表达LBCL。项目假设:TBL1是c-Myc周转的关键调节因子
代表了一种新的和有吸引力的靶向治疗c-Myc过表达的LBCL患者的候选方案。
为了验证这一假设,我们提出了以下目标:目标1:表征TBL1/c-Myc前馈
促进c-Myc高表达LBCL细胞存活的电路。目标2:启动单一药物的Ib期试验
替加韦治疗复发/难治性cMyc过表达的LBCL患者。目标3:确定组合
最大限度地发挥替加韦治疗潜力的策略。在这个项目完成后,我们将有一个更好的
了解调控c-Myc周转的TBL1调节机制将有
开发了一种新的治疗策略来治疗这种不治之症,并将开始描述
替加维特的耐药机制。
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)
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Lapo Alinari其他文献
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{{ truncateString('Lapo Alinari', 18)}}的其他基金
Trispecific CAR-T cells targeting CD19, CD20 and CD22 to treat B-cell malignancies
靶向 CD19、CD20 和 CD22 的三特异性 CAR-T 细胞治疗 B 细胞恶性肿瘤
- 批准号:
10735096 - 财政年份:2023
- 资助金额:
$ 60.13万 - 项目类别:
Targeting c-Myc stability in c-Myc overexpressing large B-cell lymphoma
靶向 c-Myc 过表达大 B 细胞淋巴瘤中的 c-Myc 稳定性
- 批准号:
10594537 - 财政年份:2022
- 资助金额:
$ 60.13万 - 项目类别:
Targeting transducin Beta-like protein 1 in mantle cell lymphoma
套细胞淋巴瘤中的转导蛋白 Beta 样蛋白 1 靶向治疗
- 批准号:
10092821 - 财政年份:2018
- 资助金额:
$ 60.13万 - 项目类别:
Targeting transducin Beta-like protein 1 in mantle cell lymphoma
套细胞淋巴瘤中的转导蛋白 Beta 样蛋白 1 靶向治疗
- 批准号:
9505524 - 财政年份:2018
- 资助金额:
$ 60.13万 - 项目类别:
Targeting transducin Beta-like protein 1 in mantle cell lymphoma
套细胞淋巴瘤中的转导蛋白 Beta 样蛋白 1 靶向治疗
- 批准号:
10360452 - 财政年份:2018
- 资助金额:
$ 60.13万 - 项目类别:
Shared Resource 09: Leukemia Tissue Bank (LTBSR)
共享资源 09:白血病组织库 (LTBSR)
- 批准号:
10553341 - 财政年份:1997
- 资助金额:
$ 60.13万 - 项目类别:
Shared Resource 09: Leukemia Tissue Bank (LTBSR)
共享资源 09:白血病组织库 (LTBSR)
- 批准号:
10333297 - 财政年份:1997
- 资助金额:
$ 60.13万 - 项目类别:
Shared Resource 09: Leukemia Tissue Bank (LTBSR)
共享资源 09:白血病组织库 (LTBSR)
- 批准号:
10090012 - 财政年份:1997
- 资助金额:
$ 60.13万 - 项目类别:














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