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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.

总结