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.
总结

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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