Project 3: Targeting PRMT5 in Mantle Cell Lymphoma

项目3：针对套细胞淋巴瘤的PRMT5

基本信息

批准号：
10478985
负责人：
Robert Alan Baiocchi
金额：
$ 26.52万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-18 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10478985
关键词：
Address Affect Animal Model Antibodies Arginine B-Cell Antigen Receptor B-Cell Lymphomas B-Cell NonHodgkins Lymphoma B-Lymphocytes Cell Cycle Cell Cycle Progression ChIP-seq Chemicals Chromatin Chromatin Remodeling Factor Clinic Clinical Trials Collaborations Combined Modality Therapy Complex Critical Pathways Cyclin D1 DNA Methylation DNA Modification Methylases DNMT3a Data Diagnosis Disease Drug resistance Drug usage EZH2 gene Enzymes Epigenetic Process Event FOXO1A gene Family G1 Arrest Gene Expression Gene Silencing Genetic Genome Mappings Growth HDAC2 gene Hematologic Neoplasms Histone Deacetylase Hypermethylation Immune Lead Lymphocyte Activation Lymphoma Lymphoma cell Lysine Malignant Neoplasms Mantle Cell Lymphoma Mediating Methyltransferase MicroRNAs Modeling Molecular Target Mutate Outcome PI3K/AKT Pathogenesis Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Pre-Clinical Model Proliferating Protein Binding Domain Protein Dephosphorylation Protein Inhibition Protein-Arginine N-Methyltransferase Proto-Oncogene Proteins c-akt RB1 gene RBL2 gene Receptor Signaling Refractory Regulation Regulator Genes Regulatory Pathway Repression Resistance Resistance development Rest Role Signal Pathway Signal Transduction Stem cell transplant TP53 gene Testing Therapeutic Therapeutic Agents Toxic effect Translations Tumor Suppressor Genes Tumor Suppressor Proteins Work XCL1 gene anti-cancer anticancer activity arginyllysine base cancer gene expression cdc Genes chemotherapy epigenetic regulation epigenome epigenomics genetic corepressor genome-wide histone methylation improved improved outcome in vivo in vivo Model inhibitor inhibitor therapy innovation insight knock-down neoplastic cell novel novel strategies novel therapeutic intervention novel therapeutics overexpression pre-clinical prevent programs restoration small hairpin RNA synergism t(11 14)(q13 q32)targeted agent targeted treatment therapeutic target transcriptome sequencing tumor whole genome

项目摘要

Project 3 Summary Mantle cell lymphoma (MCL) is an incurable B-cell lymphoma characterized by aberrant genetic and epigenetic events. A variety of therapeutic strategies have been used to improve the outcome of MCL patients including immune-chemotherapy and stem cell transplantation. Approaches targeting the B cell receptor (BCR) signaling pathway with ibrutinib have shown promise, however, outcome data is immature and emerging resistance is clearly evident. Thus there remains a clear, unmet need for novel therapeutic approaches for treating MCL. We have shown that PRMT5 is selectively over expressed in MCL and drives global repressive epigenetic marks on chromatin to silence regulatory and tumor suppressor genes. PRMT5 knock down with shRNA promotes selective MCL toxicity which led us to hypothesize that PRMT5 is an attractive target for this disease. We have developed a “first-in-class” drug that selectively inhibits PRMT5 activity with IC50 in low nM range. Our lead drug is toxic to lymphoma, not normal B cells, is well tolerated in vivo with impressive anti-tumor activity in preclinical animal models of MCL. PRMT5 inhibitors have been used as chemical probes to dissect out critical pathways utilized by MCL tumor cells. Preliminary whole genome mapping with antibodies specific for PRMT5 epigenetic marks and whole transcriptome sequencing (RNA-Seq, in collaboration with WCM) in presence and absence of PRMT5 inhibitors has revealed a broad range of signaling, survival and growth pathways to be governed by this enzyme. Our preliminary work has found that PRMT5 directly targets regulatory genes such as PTPROt, TRIB3, and PIK3IP1 which negatively regulate BCR and PI3K/AKT pathways. Inactivation of constitutive AKT activity leads to dephosphorylation of FOXO1, promoting its epigenetic regulation of anti- cancer gene expression. We discovered that PRMT5 inhibition leads to direct de-repression of multiple micro- RNAs that may deplete CYCLIN D1 leading to activation of RB and restoration of the RB/E2F regulatory network. Consequently, PRMT5 inhibition leads to RB/E2F-mediated silencing of EZH2, SUZ12 and EED, components of the epigenetic repressor PRC2 complex, a family of lysine methyltransferase enzymes that are frequently mutated and activated in MCL. Thus, by inhibiting PRMT5, we can achieve direct inhibition of repressive arginine epigenetic marks while indirectly depleting lysine repressive marks like H3K27(Me3) and possibly, targets of FOXO1. Our strategy to inhibit a central player like PRMT5 has led to a novel approach to restore regulation to the MCL cell at multiple levels including the epigenome, BCR, PI3K/AKT, and CYCLIN D/RB-E2F pathways. We have proposed integrative whole genome approaches and strategies utilizing innovative preclinical MCL models to examine how PRMT5 inhibition can circumvent drug resistance encountered with novel molecularly targeted agents examined in clinical trials and preclinical work proposed in Projects 1 and 2. We present an innovative, straight-forward and robust approach to discover the genetic programs altered in MCL and will use this information to develop new strategies to treat this incurable disease.

项目3总结套细胞淋巴瘤 (MCL) 是一种无法治愈的 B 细胞淋巴瘤，其特征是异常遗传和表观遗传多种治疗策略已被用来改善 MCL 患者的预后，包括针对 B 细胞受体 (BCR) 信号传导的免疫化疗和干细胞移植方法。依鲁替尼途径已显示出希望，然而，结果数据尚不成熟，并且新出现的耐药性因此，对于治疗 MCL We 的新治疗方法仍然存在明确的、未满足的需求。研究表明 PRMT5 在 MCL 中选择性过度表达并驱动全局抑制性表观遗传标记染色质上的沉默调节基因和抑癌基因可通过 shRNA 促进 PRMT5 敲低。选择性 MCL 毒性使我们认识到 PRMT5 是治疗这种疾病的一个有吸引力的靶标。开发了一种“一流”药物，可选择性抑制 PRMT5 活性，IC50 在低 nM 范围内。该药物对淋巴瘤（而非正常 B 细胞）有毒，体内耐受性良好，在体内具有令人印象深刻的抗肿瘤活性 PRMT5 抑制剂的临床前动物模型已被用作化学探针来剖析关键问题。 MCL 肿瘤细胞利用 PRMT5 特异性抗体进行初步全基因组图谱。表观遗传标记和全转录组测序（RNA-Seq，与 WCM 合作）的存在和 PRMT5抑制剂的缺失揭示了广泛的信号传导、生存和生长途径我们的初步工作发现 PRMT5 直接靶向诸如此类的调控基因。如 PTPROt、TRIB3 和 PIK3IP1，它们负向调节 BCR 和 PI3K/AKT 通路的失活。组成型 AKT 活性导致 FOXO1 去磷酸化，促进其表观遗传调控我们发现 PRMT5 抑制会导致多个微分子的直接去抑制。可能消耗 CYCLIN D1 导致 RB 激活和 RB/E2F 调节恢复的 RNA 网络检查发现，PRMT5 抑制导致 RB/E2F 介导的 EZH2、SUZ12 和 EED 沉默，表观遗传阻遏物 PRC2 复合物的组成部分，PRC2 复合物是赖氨酸甲基转移酶家族 MCL 中频繁突变和激活，因此，通过抑制 PRMT5，我们可以实现直接抑制。抑制精氨酸表观遗传标记，同时间接消耗赖氨酸抑制标记，如 H3K27(Me3) 和可能是 FOXO1 的目标，我们抑制 PRMT5 这样的核心角色的策略已经导致了一种新颖的方法。在多个层面上恢复对 MCL 细胞的调节，包括表观基因组、BCR、PI3K/AKT 和 CYCLIN 我们提出了利用 D/RB-E2F 途径的综合全基因组方法和策略。创新的临床前 MCL 模型来研究 PRMT5 抑制如何规避耐药性遇到了在临床试验和临床前工作中检查的新型分子靶向药物项目 1 和 2。我们提出了一种创新、直接且稳健的方法来发现遗传 MCL 的项目发生了改变，并将利用这些信息来制定治疗这种不治之症的新策略。