BET protein antagonist-based targeted therapy of Mantle Cell Lymphoma

基于BET蛋白拮抗剂的套细胞淋巴瘤靶向治疗

基本信息

批准号：
10132260
负责人：
KAPIL BHALLA
金额：
$ 39.01万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10132260
关键词：
Agammaglobulinaemia tyrosine kinase Apoptosis B-Cell Antigen Receptor B-Lymphocytes BCL2 gene BIRC3 gene Binding Bromodomain CDK4 gene CDKN2A gene Cell Line Cell Survival Clinical Complement Factor B DNA Polymerase II DNA Sequence Alteration Development Disease remission Elongation Factor Enhancers Exhibits G1/S Checkpoint Pathway Gene Expression Genes Genetic Transcription Growth Histones Human IKBKB Immuno-Chemotherapy In Vitro Lead Lymphoma cell Lysine MYC gene Malignant Neoplasms Mantle Cell Lymphoma Mediating Messenger RNA Mus Mutation Nuclear Observational Study Oncogenes Oncoproteins Pathway interactions Patients Protac Proteins RELA gene RNA Receptor Signaling Refractory Regulator Genes Reporting Resistance Signal Transduction TRAF2 gene Testing Transcript Tyrosine Kinase Inhibitor Xenograft procedure base bcl-1 Genes cell growth clinically relevant genetic signature improved in vivo inhibitor/antagonist kinase inhibitor lymph nodes neoplastic cell novel patient derived xenograft model potential biomarker pre-clinical prevent promoter prototype recruit research clinical testing response targeted treatment tumor ubiquitin-protein ligase

项目摘要

Project Summary: Mantle Cell Lymphoma (MCL) cells exhibit genetic alterations involving the cell cycle G1/S checkpoint- regulatory genes cyclin D1, CDKN2A, CDK4, as well as the cell growth and survival genes MYC and BCL2. MCL cells also display increased B cell receptor signaling and transcriptional activity of NFkB, making them sensitive to the lethal activity of the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib. Whereas treatment with ibrutinib induces clinical responses and improves survival, primary refractoriness or eventual emergence of resistance to ibrutinib is common, preventing durable remissions in MCL. Recently, mutations in CARD11/IKBKB/TRAF2/BIRC3/NIK, which lead to the activation of the classical or alternative NFkB signaling, have been documented, to confer resistance to ibrutinib. Our preliminary studies have demonstrated that treatment with the prototype BET (bromodomain and extra terminal) protein (BETP) antagonist (BETi) inhibits the mRNA and protein levels of the MCL-relevant oncogenes, including MYC, BCL-2 and CDK4/6. BETi treatment reduced the nuclear levels of NFkB, abrogated BRD4-dependent NFkB activity, and repressed its pro-growth and pro-survival target genes, including BTK, leading to apoptosis of human MCL cells. Notably, treatment with BETi alone also induced apoptosis of ibrutinib-resistant MCL cells. However, despite their promising anti-tumor activity, treatment with BETi leads to BRD4 protein accumulation, which limits BETi- mediated inhibition of the MCL-relevant oncoproteins including NFkB, thereby reducing the antitumor activity of BETi treatment. However, we have recently determined that treatment with the hetero-bifunctional BETP- PROTAC (Proteolysis Targeting Chimera), e.g., ARV-825 or ARV-771, which recruit BETPs to the E3 ubiquitin ligase cereblon or VHL, respectively, causes efficient, and prolonged degradation of BRD4, leading to inhibition of the MCL-relevant oncoproteins including NFkB. Based on this, we hypothesize that treatment with BETP- PROTAC will induce significantly more apoptosis than BETi, as well as exert synergistic lethality and anti- tumor efficacy with ibrutinib or with anti-BCL2 or CDK4/6 kinase inhibitor against cultured and patient-derived (PD) primary MCL cells. In AIM 1, we will determine the in vitro lethal activity and elucidate its predictive minimal signature of genetic-mutations and gene-expression perturbations due to the BETP-PROTACs (ARV- 825 and ARV-771) versus clinically-relevant BETis (OTX015 and ABBV-075), alone and in combination with ibrutinib in cultured cell lines as well as patient-derived (PD), genetically-profiled, primary MCL cells. In AIM 2, we will determine the combined in vitro lethal activity, and its predictive minimal gene-expression perturbations signature, due to treatment with the combinations of BET-PROTAC versus BETi with anti-BCL2 or anti-CDK4/6 inhibitor against the cultured and genetically-profiled, PD, ibrutinib-sensitive (IS) or ibrutinib-persister/resistant (IR) MCL cells. In AIM 3, we will determine the in vivo efficacy of co-treatment with ARV-771 or ABBV-075 and venetoclax or palbociclib, utilizing the cultured cell line and PD xenograft (PDX) models of IS or IR MCL cells.

项目概要：套细胞淋巴瘤 (MCL) 细胞表现出涉及细胞周期 G1/S 检查点的遗传改变 - 调节基因cyclin D1、CDKN2A、CDK4，以及细胞生长和存活基因MYC和BCL2。 MCL 细胞还表现出增强的 B 细胞受体信号传导和 NFkB 转录活性，使其对布鲁顿酪氨酸激酶 (BTK) 抑制剂依鲁替尼的致死活性敏感。依鲁替尼诱导临床反应并改善生存率、原发性难治性或最终出现对依鲁替尼的耐药性很常见，阻碍了 MCL 的持久缓解。 CARD11/IKBKB/TRAF2/BIRC3/NIK，导致经典或替代 NFkB 信号传导的激活，已被记录，赋予依鲁替尼耐药性。用原型 BET（溴结构域和额外末端）蛋白 (BETP) 拮抗剂 (BETi) 治疗可抑制 MCL 相关癌基因的 mRNA 和蛋白质水平，包括 MYC、BCL-2 和 CDK4/6。治疗降低了 NFkB 的核水平，消除了 BRD4 依赖性 NFkB 活性，并抑制了其促生长和促存活靶基因，包括 BTK，导致人类 MCL 细胞凋亡。单独使用 BETi 治疗也能诱导伊布替尼耐药的 MCL 细胞凋亡。由于 BETi 具有良好的抗肿瘤活性，因此使用 BETi 治疗会导致 BRD4 蛋白积累，从而限制了 BETi- 介导抑制 MCL 相关癌蛋白（包括 NFkB），从而降低其抗肿瘤活性然而，我们最近确定使用异双功能BETP-进行治疗。 PROTAC（蛋白水解靶向嵌合体），例如 ARV-825 或 ARV-771，将 BETP 募集至 E3 泛素连接酶 cereblon 或 VHL 分别导致 BRD4 有效且长时间的降解，从而导致抑制包括 NFkB 在内的 MCL 相关癌蛋白的研究基于此，我们用 BETP- 进行治疗。 PROTAC 将比 BETi 诱导更多的细胞凋亡，并发挥协同致死作用和抗- 依鲁替尼或抗 BCL2 或 CDK4/6 激酶抑制剂对培养物和患者来源的肿瘤疗效 (PD) 原代 MCL 细胞在 AIM 1 中，我们将确定体外致死活性并阐明其预测。由于 BETP-PROTAC（ARV- 825 和 ARV-771）与临床相关的 BETis（OTX015 和 ABBV-075），单独使用或联合使用在 AIM 2 中，培养细胞系以及患者来源 (PD)、基因分析的原代 MCL 细胞中的依鲁替尼。我们将确定组合的体外致死活性及其预测的最小基因表达扰动特征，归因于 BET-PROTAC 与 BETi 与抗 BCL2 或抗 CDK4/6 组合的治疗针对培养和基因分析、PD、依鲁替尼敏感 (IS) 或依鲁替尼持续/耐药的抑制剂 (IR) MCL 细胞，在 AIM 3 中，我们将确定与 ARV-771 或 ABBV-075 联合治疗的体内功效和 venetoclax 或 palbociclib，利用 IS 或 IR MCL 细胞的培养细胞系和 PD 异种移植 (PDX) 模型。