Therapeutic targeting of RNA splicing catalysis through inhibition of Protein Arginine Methylation

通过抑制蛋白质精氨酸甲基化来治疗 RNA 剪接催化

基本信息

批准号：
10393007
负责人：
Ernesto Guccione
金额：
$ 38.36万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10393007
关键词：
Acute Myelocytic Leukemia Alleles Antisense Oligonucleotides Arginine Catalysis Cells Chronic Lymphocytic Leukemia Data Disease Drug Targeting Dysmyelopoietic Syndromes Evaluation Event Gene Expression Genes Genetic Health In Vitro Individual Leukemic Cell Malignant Neoplasms Mediating Methylation Modeling Molecular Mutation Myeloid Leukemia Patients Pharmaceutical Preparations Pharmacology Phase Phase I Clinical Trials Phenotype Point Mutation Process Protein Inhibition Protein Splicing Protein-Arginine N-Methyltransferase Proteins Proteome RNA Splicing RNA methylation RNA-Binding Proteins RNA-targeting therapy Refractory Safety Small Nuclear Ribonucleoproteins Solid Neoplasm Spliceosome Assembly Pathway Spliceosomes Therapeutic Therapeutic Effect Uveal Melanoma Work cancer cell cancer type cell killing clinical development curative treatments early phase clinical trial efficacy evaluation in vivo inhibitor leukemia mRNA Precursor mutant myeloid leukemia cell novel therapeutic intervention novel therapeutics preclinical development small molecule snRNP Structural Core Protein

项目摘要

SUMMARY Mutations in splicing factors (SF) are highly enriched in a variety of cancer types, particularly myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic lymphocytic leukemia (CLL), in addition to solid tumors such as uveal melanoma. Our group has identified that cells bearing SF mutations cannot tolerate further perturbations to splicing catalysis and, consistent with this, we have identified that spliceosomal mutant cancer cells are preferentially sensitive to small molecules that disrupt pre-mRNA splicing. While the above effort has resulted in an ongoing phase I clinical trial of a spliceosome modulatory compound for patients with refractory myeloid leukemias, we do not currently know the safety or efficacy of pharmacologic modulation of core spliceosome function. To this end, our group has also recently identified that inhibiting spliceosomal assembly through inhibition of arginine methylation of Sm proteins provides an alternate means of therapeutic splicing inhibition. We have identified that inhibiting either symmetric arginine methylation (mediated by the protein arginine methyltransferase 5 (PRMT5)) or asymmetric dimethyl arginine methylation (mediated by type I PRMTs (PRMT1, 4, and 6)) reduces splicing fidelity resulting in strong preferential killing of SF-mutant leukemias over their wildtype counterparts. Here we aim to determine if in leukemia, SF-mutations portend greater vulnerability to a “second hit” targeting splicing through inhibition of type I (PRMT1/4/6) and/or type II (PRMT5) PRMTs. In Aim 1 we will define the therapeutic potential of inhibiting PRMT5, type I PRMTs, and core spliceosome function, alone or together in leukemia models with or without a SF mutation. In addition, we will understand the consequences of combined PRMT inhibition on RNA splicing and gene expression relative to inhibiting PRMT5 or Type I PRMTs alone. In parallel to the above studies, in Aim 2, we will define the molecular basis for the cooperation between PRMT inhibition and SF mutations, by first determining the methylation substrates of PRMT5 or Type I PRMTs, and secondly by determining if individual spliceosomal changes mediated by inhibiting PRMTs or core spliceosome function can be mimicked by anti-sense oligonucleotides, thereby providing an orthogonal novel therapeutic approach to eliminate SF-mutant cancer cells. The significance of these studies is that inhibitors of PRMTs are now entering phase I clinical trials in patients with a variety of cancer types and defining the mechanistic effects and therapeutic utility of PRMT inhibitors for specific genetic subsets of cancers may have incredible therapeutic importance. The health relatedness is that our studies may identify new therapeutic opportunities for a variety of cancer types that have no curative therapies for the majority of patients with these diseases currently.

概括剪接因子（SF）的突变在多种癌症类型中高度富集，尤其是骨髓增生除固体外肿瘤，例如卵子黑色素瘤。我们的小组已经确定带有SF突变的细胞无法忍受对剪接催化的进一步扰动，并且与此相一致，我们已经确定了剪接突变体癌细胞优选对破坏前MRNA剪接的小分子敏感。虽然上述努力导致了一项持续的I期临床试验的剪接调节化合物对于难治性髓样白血病的患者，我们目前不知道药理的安全性或效率核心剪接体功能的调制。为此，我们的小组最近还确定了抑制通过抑制SM蛋白精氨酸甲基化的剪接体组装提供了一种替代手段理论剪接抑制。我们已经确定抑制任何一种对称精氨酸甲基化（由蛋白精氨酸甲基转移酶5（PRMT5）或非对称二甲基精氨酸甲基化介导（由I型PRMT（PRMT1、4和6）介导）降低了剪接保真度，导致强烈的优先杀戮 SF突变的白血病在其野生型对应物上。在这里，我们旨在确定在白血病中，SF-Mutations是否预示着“第二击”目标的更大脆弱性通过抑制I型（PRMT1/4/6）和/或II型（PRMT5）PRMT进行剪接。在AIM 1中，我们将定义抑制PRMT5，I型PRMT和核心剪接体功能的治疗潜力，单独或一起白血病模型有或没有SF突变。此外，我们将了解联合的后果 PRMT抑制RNA剪接和基因表达相对于仅抑制PRMT5或I型PRMT的抑制。与上述研究同时，在AIM 2中，我们将定义PRMT合作的分子基础抑制和SF突变，首先确定PRMT5或I型PRMT的甲基化底物，并其次，通过确定是否通过抑制PRMT或核心剪接体介导的单个剪接体变化可以通过反义寡核苷酸模仿功能，从而提供正交的新疗法消除SF突变癌细胞的方法。这些研究的意义在于，PRMT的抑制剂现在正在进入患者的I期临床试验使用多种癌症类型，并定义PRMT抑制剂的机械效应和热效用癌症的特定遗传亚集可能具有令人难以置信的治疗意义。健康相关性是我们的研究可能会发现没有治愈性的各种癌症类型的新治疗机会目前，大多数这些疾病患者的疗法。