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.
项目概要
双打击 (DH) 和三打击 (TH) 淋巴瘤 (L) 是罕见的高级别 B 细胞淋巴瘤,伴有弥漫性大 B 细胞
(DLBCL)形态特征是涉及 MYC 的染色体易位同时发生,
BCL2和/或BCL6。具有双重 c-Myc(>40%,通过免疫组织化学,IHC)和 BCL2(>50%,通过 IHC)的 DLBCL
没有易位的蛋白质过表达(双表达子或 DEL)明显比
DH/THL,占DLBCL患者的20%~30%。具有 DEL、DHL 或 THL 的淋巴瘤在这里
统称为 c-Myc 过表达 LBCL,与 c-Myc 相比,预后明显较差
Myc 阴性对照 [3 年总生存率分别约为 30% 和 70%]。临床较差
这部分淋巴瘤患者的结果凸显了对新治疗策略的需求。转导蛋白
β 样蛋白 1 (TBL1X) 最初被鉴定为一种特定的接头蛋白,在
通过将 β-连环蛋白招募到 Wnt 靶标(例如 MYC 和)的启动子区域来实现经典 Wnt 信号传导
CCND1 激活它们的转录。很少有发表的报告表明 Wnt/β-catenin 信号传导是
DLBCL 中持续激活,这促使我们对该疾病进行初步研究。初步数据:我们的
已发表的研究表明,与正常 B 细胞不同,DLBCL 细胞表达丰富水平的 TBL1。遗传
删除 TBL1 或使用一流的小分子靶向药物 tegavivint (Iterion) 进行药物治疗
TBL1 在体外和体内诱导显着的 DLBCL 细胞死亡。虽然 tegavivint 最初是作为一种
TBL1/β-连环蛋白相互作用的抑制剂,我们的数据表明,TBL1 的基因缺失和用
tegavivint 以转录后/β-连环蛋白独立的方式降低 c-Myc 蛋白表达。我们进一步
表明在 DLBCL 中,TBL1 与 Skp1/Cul1/F-Box (SCF) 超复合体相互作用,该复合体控制
蛋白酶体介导的关键促生存蛋白(例如 c-Myc 和 mTOR 成分)的降解
信号传导如Rheb。总的来说,这些观察结果确立了将 TBL1 作为一种新型药物的基本原理。
促进 c-Myc 周转并扰乱由其在 c-中的活性协调的驱动事件的治疗策略
Myc 过度表达 LBCL。项目假设:TBL1 作为 c-Myc 更新的关键调节剂
代表了 c-Myc 过表达 LBCL 患者靶向治疗的新颖且有吸引力的候选者。
为了检验这一假设,我们提出以下目标: 目标 1:表征 TBL1/c-Myc 前馈
促进 c-Myc 过表达 LBCL 细胞存活的电路。目标 2:启动单药 Ib 期试验
tegavivint 用于治疗复发/难治性 cMyc 过表达 LBCL 患者。目标 3:识别组合
最大化 tegavivint 治疗潜力的策略。当这个项目完成后,我们将拥有更好的
了解 TBL1 调节 c-Myc 周转率的调节机制,将有
开发了一种新的治疗策略来治疗这种不治之症,并将开始表征
tegavivint 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)
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 }}
Lapo Alinari其他文献
Lapo Alinari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('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: