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: 10342915
• 负责人: Lapo Alinari
• 金额: $ 60.13万
• 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/10342915
• 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; Pharmacology; 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; base; beta catenin; c-myc Genes; in vivo; in vivo Model; inhibitor; knock-down; multicatalytic endopeptidase complex; novel; novel strategies; novel therapeutic intervention; overexpression; 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。