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：
10249089
负责人：
Robert Alan Baiocchi
金额：
$ 27.06万
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10249089
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/antagonist 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摘要地幔细胞淋巴瘤（MCL）是一种无法治愈的B细胞淋巴瘤，其特征是异常的遗传和表观遗传学事件。已使用多种治疗策略来改善MCL患者的结果免疫化学疗法和干细胞移植。靶向B细胞受体（BCR）信号传导的方法 ibrutinib的途径已经显示出希望，但是，结果数据不成熟，新兴的抵抗力为显然证据。对于治疗MCL的新型热方法仍然存在清晰，未满足的需求。我们已经证明PRMT5在MCL中有选择地表达并驱动全局反射性表观遗传标记在染色质到静音调节和肿瘤抑制基因上。 prmt5用shRNA击倒促进选择性MCL毒性导致我们假设PRMT5是该疾病的有吸引力的靶标。我们有开发了一种“一流”药物，该药物在低NM范围内有选择地抑制IC50的PRMT5活性。我们的领导药物对淋巴瘤有毒，而不是正常B细胞，在体内耐受性良好，具有令人印象深刻的抗肿瘤活性 MCL的临床前动物模型。 PRMT5抑制剂已被用作化学问题来剖析关键 MCL肿瘤细胞利用的途径。具有特定于PRMT5的抗体的初步整体基因组映射表观遗传标记和整个转录组测序（RNA-Seq，与WCM合作） PRMT5抑制剂的缺乏揭示了广泛的信号传导，生存和生长途径由该酶支配。我们的初步工作发现，PRMT5直接针对调节基因如PTPROT，TRIB3和PIK3IP1，对BCR和PI3K/AKT途径负面调节。失活组成型AKT活性导致FOXO1的磷酸化，从而促进其抗遗传调节癌基因表达。我们发现PRMT5抑制导致多个微型 - 可能与Cyclin D1不同的RNA导致RB激活和RB/E2F调节的恢复网络。因此，PRMT5抑制会导致RB/E2F介导的EZH2，SUZ12和EED的沉默，表观遗传复制品PRC2复合物的成分，这是一种赖氨酸甲基转移酶家族，是经常在MCL中突变并激活。通过抑制PRMT5，我们可以直接抑制抑制精氨酸表观遗传标记，同时间接耗尽赖氨酸反射标记，例如H3K27（ME3）和可能是FOXO1的目标。我们抑制像PRMT5这样的中心参与者的策略已导致一种新颖的方法在多个级别上恢复对MCL细胞的调节，包括表观基因组，BCR，PI3K/AKT和细胞周期蛋白 D/RB-E2F途径。我们已经提出了使用的整体基因组方法和策略创新的临床前MCL模型检查PRMT5抑制如何避免耐药性在临床试验和提出的临床前工作中检查的新型分子靶向剂遇到项目1和2。我们提出了一种创新，直率和强大的方法来发现通用 MCL的计划发生了变化，将使用此信息制定新的策略来治疗这种无法治愈的疾病。