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

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.
摘要 剪接因子(SF)突变在多种癌症类型中高度丰富,尤其是骨髓增生异常 综合征(MDS)、急性髓系白血病(AML)和慢性淋巴细胞白血病(CLL) 葡萄膜黑色素瘤等肿瘤。我们的团队已经发现携带SF突变的细胞不能耐受 对剪接催化的进一步干扰,与此一致,我们已经鉴定出剪接体突变体 癌细胞对干扰前信使核糖核酸剪接的小分子更敏感。 虽然上述努力已经导致正在进行的剪接体调节化合物的I期临床试验 对于难治性髓系白血病患者,我们目前还不知道药物的安全性或有效性。 核心剪接体功能的调节。为此,我们的小组最近也发现,抑制 通过抑制Sm蛋白精氨酸甲基化进行剪接体组装提供了一种替代手段 治疗性剪接抑制。我们已经发现,抑制对称的精氨酸甲基化 (由蛋白质精氨酸甲基转移酶5(PRMT5)介导)或不对称二甲基精氨酸甲基化 (由I型PRMT(PRMT1、4和6)介导)会降低剪接保真度,从而导致强烈的优先杀伤 SF-突变型白血病优于野生型白血病。 在这里,我们的目标是确定在白血病中,SF突变是否预示着更容易受到“二次打击”的影响 通过抑制I型(PRMT1/4/6)和/或II型(PRMT5)PRMTs进行剪接。在目标1中,我们将定义 单独或联合抑制PRMT5、I型PRMTs和核心剪接体功能的治疗潜力 带有或不带有SF突变的白血病模型。此外,我们将了解合并后的后果 PRMT对RNA剪接和基因表达的抑制作用与单独抑制PRMT5或I型PRMT有关。 在上述研究的同时,在目标2中,我们将确定PRMT之间合作的分子基础 抑制和SF突变,通过首先确定PRMT5或I型PRMTs的甲基化底物,以及 其次,通过确定个体剪接体的改变是否由抑制PRMTs或核心剪接体介导 功能可以被反义寡核苷酸模拟,从而提供一种正交的新型治疗方法 消除SF突变癌细胞的方法。 这些研究的意义在于,PRMTs的抑制剂现在正在进入患者的I期临床试验。 各种癌症类型,并确定PRMT抑制剂的机制效应和治疗效用 癌症的特定基因亚群可能具有令人难以置信的治疗重要性。与健康相关的是 我们的研究可能会为各种无法治愈的癌症类型找到新的治疗机会 目前这些疾病的大多数患者都有治疗方法。

项目成果

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Ernesto Guccione其他文献

Ernesto Guccione的其他文献

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{{ truncateString('Ernesto Guccione', 18)}}的其他基金

Implementation of a qPCR-based assay for the quantification of SARS-CoV-2-specific T cells in immunocompromised patients
实施基于 qPCR 的检测方法,对免疫功能低下患者的 SARS-CoV-2 特异性 T 细胞进行定量
  • 批准号:
    10580531
  • 财政年份:
    2023
  • 资助金额:
    $ 38.36万
  • 项目类别:
FUNCTIONAL CHARACTERIZATION OF NOVEL DETERMINANTS OF HOLOPROSENCEPHALY (HPE)
前脑无裂畸形 (HPE) 的新决定因素的功能特征
  • 批准号:
    10366059
  • 财政年份:
    2021
  • 资助金额:
    $ 38.36万
  • 项目类别:
Resource Core D - Bioinformatics and Statistical Analysis Core
资源核心 D - 生物信息学和统计分析核心
  • 批准号:
    10676795
  • 财政年份:
    2021
  • 资助金额:
    $ 38.36万
  • 项目类别:
FUNCTIONAL CHARACTERIZATION OF THE PRDM10-ZN FINGER TRANSCRIPTION FACTOR IN EARLY MAMMALIAN DEVELOPMENT
PRDM10-ZN 指转录因子在早期哺乳动物发育中的功能特征
  • 批准号:
    10477941
  • 财政年份:
    2021
  • 资助金额:
    $ 38.36万
  • 项目类别:
Resource Core D - Bioinformatics and Statistical Analysis Core
资源核心 D - 生物信息学和统计分析核心
  • 批准号:
    10463725
  • 财政年份:
    2021
  • 资助金额:
    $ 38.36万
  • 项目类别:
FUNCTIONAL CHARACTERIZATION OF NOVEL DETERMINANTS OF HOLOPROSENCEPHALY (HPE)
前脑无裂畸形 (HPE) 的新决定因素的功能特征
  • 批准号:
    10596128
  • 财政年份:
    2021
  • 资助金额:
    $ 38.36万
  • 项目类别:
FUNCTIONAL CHARACTERIZATION OF THE PRDM10-ZN FINGER TRANSCRIPTION FACTOR IN EARLY MAMMALIAN DEVELOPMENT
PRDM10-ZN 指转录因子在早期哺乳动物发育中的功能特征
  • 批准号:
    10617819
  • 财政年份:
    2021
  • 资助金额:
    $ 38.36万
  • 项目类别:
DISSECTING THE ROLE OF PRDM15 IN NORMAL HEMATOPOIESIS AND B-CELL MALIGNANCIES
剖析 PRDM15 在正常造血和 B 细胞恶性肿瘤中的作用
  • 批准号:
    10316262
  • 财政年份:
    2020
  • 资助金额:
    $ 38.36万
  • 项目类别:
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
  • 批准号:
    10165673
  • 财政年份:
    2020
  • 资助金额:
    $ 38.36万
  • 项目类别:
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
  • 批准号:
    10703206
  • 财政年份:
    2020
  • 资助金额:
    $ 38.36万
  • 项目类别:

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