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）是罕见的高级别B细胞淋巴瘤，伴有弥漫性大B细胞浸润。 （DLBCL）形态学特征在于涉及MYC的染色体易位的共现， BCL 2和/或BCL 6。具有双重c-Myc（免疫组织化学，IHC>40%）和BCL 2（IHC>50%）的DLBCL 无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%。淋巴瘤要么DEL，DHL，或THL在这里 统称为c-Myc过表达LBCL，与c-Myc过表达LBCL相比，预后显著更差。 Myc阴性对照[3年总生存率分别为~30%和70%]。可怜的临床 淋巴瘤患者的这一亚组的结果突出了对新的治疗策略的需要。转导素 β-样蛋白1（TBL 1X）最初被鉴定为一种特异性接头蛋白，在细胞凋亡中起重要作用。 通过将β-连环蛋白募集到Wnt靶点如MYC的启动子区来进行经典Wnt信号传导， CCND 1激活其转录。很少有发表的报道表明Wnt/β-catenin信号转导是 在DLBCL中组成性激活，这促使我们对这种疾病进行初步研究。数据来源：Our 公开的工作表明，与正常B细胞不同，DLBCL细胞表达丰富水平的TBL 1。遗传 TBL 1缺失或使用tegavivint（IEGM）进行药物治疗，这是一种一流的小分子靶向 TBL 1在体外和体内诱导显著的DLBCL细胞死亡。虽然tegavivint最初是作为一种 TBL 1/β-连环蛋白相互作用的抑制剂，我们的数据显示TBL 1的遗传缺失和用 tegavivint以转录后/β-连环蛋白非依赖性方式降低c-Myc蛋白表达。我们进一步 显示在DLBCL中，TBL 1与Skp 1/Cul 1/F-Box（SCF）超复合物相互作用，该超复合物控制DLBCL的发生。 蛋白酶体介导的关键促存活蛋白如c-Myc和mTOR组分的降解 信号，如Rheb。总的来说，这些观察结果建立了靶向TBL 1作为新的治疗方法的基本原理。 治疗策略，以促进c-Myc周转，并破坏由其在c-Myc中的活性协调的驱动事件。 Myc过表达LBCL。项目假设：TBL 1作为c-Myc周转的关键调节剂， 代表了一种新的和有吸引力的候选人的c-Myc过表达LBCL患者的靶向治疗。 为了验证这一假设，我们提出了以下目标：目标1：表征TBL 1/c-Myc前馈 促进过表达c-Myc的LBCL细胞存活的回路。目标2：启动单药Ib期试验 在复发性/难治性cMyc过表达LBCL患者中使用替加维因特。目标3：确定组合 最大化tegavivint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TBL 1调节c-Myc周转的机制，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 对tegavivint的耐药机制。