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
• 负责人: Lapo Alinari
• 金额: $ 55.92万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10594537
• 关键词: Accounting; Adaptor Signaling Protein; Address; B-Cell Lymphomas; B-Lymphocytes; BCL2 gene; BCL6 gene; CCND1 gene; CRISPR screen; Cell Death; Cell Survival; Cells; Cellular Morphology; Chromosomal translocation; Clinical; Complex; Data; Diffuse; Disease; Disease model; Event; F Box Domain; FRAP1 gene; Genetic; Genetic Transcription; Immuno-Chemotherapy; Immunohistochemistry; Immunologics; In Vitro; Institution; Investigation; Lead; Lymphoma; Lymphoma cell; Mediating; Methods; Molecular; Oncogenic; Oncoproteins; Outcome; Pathway interactions; Patients; Pattern; Pharmacological Treatment; Phase Ib Trial; Play; Pre-Clinical Model; Prognosis; Promoter Regions; Protein Overexpression; Proteins; Proto-Oncogene Proteins c-myc; Publishing; Refractory; Relapse; Reporting; Role; Safety; Signal Transduction; Testing; Therapeutic; Transducin; WNT Signaling Pathway; Work; beta catenin; c-myc Genes; in vivo; in vivo Model; inhibitor; knock-down; multicatalytic endopeptidase complex; novel; novel strategies; novel therapeutic intervention; overexpression; pharmacologic; posttranscriptional; potential biomarker; predicting response; programs; protein expression; recruit; resistance mechanism; response; small molecule; targeted treatment

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 双重（DH）和三重（Th）淋巴瘤（L）是罕见的高级B细胞淋巴瘤，具有弥漫性大B细胞 （DLBCL）形态的特征是涉及MYC的染色体易位的同时存在 Bcl2和/或Bcl6。具有双C-MYC的DLBCL（通过免疫组织化学，IHC> 40％）和BCL2（IHC> 50％） 蛋白质过表达无易位（双表达或DEL）比 DH/THL，占DLBCL患者的20％至30％。带有DEL，DHL或THL的淋巴瘤在这里 与C-相比 MYC阴性对应物[3年总​​生存率分别约为30％和70％]。不良的临床 这一子集的淋巴瘤患者的结果突出了需要新的治疗策略的需求。透明素 β样蛋白1（TBL1X）最初被鉴定为特定的衔接蛋白在 通过将β-catenin募集到Wnt靶标（例如MYC和MYC和 CCND1激活其转录。很少发布的报告表明Wnt/β-catenin信号是 在DLBCL中的组成型激活，这促使我们对该疾病进行了初步研究。初步数据：我们的 发表的工作表明，与正常的B细胞不同，DLBCL细胞表达了大量TBL1。遗传 用Tegavivint（Iterion）删除TBL1或药理学处理，这是一种一流的小分子靶向 TBL1在体外和体内诱导明显的DLBCL细胞死亡。而Tegavivint最初是作为 TBL1/β-catenin相互作用的抑制剂，我们的数据表明，TBL1的遗传缺失和处理 Tegavivint在转录后/β-catenin独立的方式中降低了C-MYC蛋白的表达。我们进一步 证明在DLBCL中，TBL1与SKP1/CUL1/F-BOX（SCF）SUPER COMPLEX相互作用，该complex控制着 蛋白酶体介导的关键促生物蛋白的降解（例如C-MYC和MTOR的成分）的降解 信号（例如Rheb）。总的来说，这些观察结果确定了将TBL1作为新颖的基本原理 促进C-MYC营业额并破坏驾驶员事件的治疗策略 MYC过表达LBCL。项目假设：TBL1是C-MYC营业额和 代表了C-MYC过表达LBCL患者的靶向治疗的新型且有吸引力的候选者。 为了检验这一假设，我们提出以下目的：目标1：表征TBL1/c-myc feedforward 促进C-MYC过表达LBCL细胞存活的电路。 AIM 2：与单个代理进行IB期试验 中继/难治性CMYC过表达LBCL的患者的Tegavivint。目标3：确定组合 最大化Tegavivint的治疗潜力的策略。完成该项目后，我们将有更好的 了解C-MYC营业额的TBL1调节机制，将具有 制定了一种新型的热策略来治疗这种无法治愈的疾病，并将开始表征 Tegavivint的电阻机制。