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

• 批准号: 9888204
• 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
• 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/9888204
• 关键词: Agammaglobulinaemia tyrosine kinase; Apoptosis; 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; Receptors, Antigen, B-Cell; Refractory; Regulator Genes; Reporting; Resistance; Signal Transduction; TRAF2 gene; Testing; Transcript; Tyrosine Kinase Inhibitor; Xenograft Model; Xenograft procedure; base; bcl-1 Genes; cell growth; clinically relevant; genetic signature; improved; in vivo; inhibitor/antagonist; kinase inhibitor; lymph nodes; neoplastic cell; novel; potential biomarker; pre-clinical; prevent; promoter; prototype; recruit; research clinical testing; response; targeted treatment; tumor; ubiquitin-protein ligase

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.

项目摘要： 地幔细胞淋巴瘤（MCL）细胞暴露了涉及细胞周期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细胞还显示出增加的B细胞受体信号传导和NFKB的转录活性，使其 对布鲁顿酪氨酸激酶（BTK）抑制剂ibrutinib的致命活性敏感。而治疗 ibrutinib诱导临床反应并提高生存率，初级磨性或事件紧急情况 对伊布鲁替尼的抗性很常见，可防止MCL持久的缓解。最近，突变中 card11/ikbkb/traf2/birc3/nik，导致经典或替代NFKB信号的激活， 已被记录为对伊布鲁替尼的会议抵抗。我们的初步研究表明 用原型BET（溴结构域和末端）蛋白（BETP）拮抗剂（BETI）治疗抑制 MCL相关癌基因的mRNA和蛋白质水平，包括MYC，BCL-2和CDK4/6。贝蒂 治疗降低了NFKB的核水平，牵引BRD4依赖性NFKB活性，并重现了其 促增长和促生存靶基因，包括BTK，导致人MCL细胞凋亡。尤其， 单独使用BETI治疗还诱导了耐二尼抗耐药的MCL细胞的凋亡。但是，dospite他们 有希望的抗肿瘤活性，用BETI治疗会导致BRD4蛋白的积累，这限制了BETI- 介导的抑制MCL - 相关癌蛋白在内，包括NFKB，从而降低了抗肿瘤活性 BETI治疗。但是，我们最近确定了用异性函数betp-的治疗 Protac（靶向嵌合体），例如ARV-825或ARV-771，将BETP募集到E3泛素 连接酶的脑或VHL分别导致brd4的有效和延长降解，导致抑制作用 包括NFKB在内的MCL相关的癌蛋白。基于此，我们假设用betp-的治疗 Protac将比BETI诱导更多的凋亡，并发挥协同的致死性和抗 ibrutinib或抗BCL2或CDK4/6激酶抑制剂的肿瘤效率针对培养和患者衍生 （PD）原代MCL细胞。在AIM 1中，我们将确定体外致命活性并阐明其预测性 由于betp-protacs引起的遗传杂种和基因表达扰动的最小特征（ARV- 825和ARV-771）与临床上的Betis（OTX015和ABBV-075），单独并与 ibrutinib在培养的细胞系中以及患者衍生的（PD），通常是原代的MCL细胞。在AIM 2中， 我们将确定体外致死活性的组合及其预测性最小基因表达扰动 签名，由于与BET-PROTAC与BETI与抗BCL2或抗CDK4/6的组合进行治疗 抑制剂针对培养和普遍的抑制剂，PD，Ibrutinib敏感（IS）或Ibrutinib-persister/抗性/抗性 （IR）MCL细胞。在AIM 3中，我们将确定与ARV-771或ABBV-075共同处理的体内效率 Venetoclax或palbociclib，使用IS或IR MIR MCL细胞的培养细胞系和PD Xenographic（PDX）模型。